Substituted 8-phenylxanthines useful as antagonists of A2B adenosine receptors

ABSTRACT

The present invention provides compounds having the formula I:                    
     X is (C 1 -C 8 )alkylene, (C 2 -C 8 )alkenylene, (C 2 -C 8 )alkynylene, wherein one of the carbon atoms in the alkylene, alkenylene or alkynylene groups is optionally replaced with a group having the formula —O—, —N(R 4 )C(O)—, —OC(O—, S—, —S(O)—or —SO 2 —, or a pharmaceutically acceptable salt thereof and pharmaceutical compositions comprising compounds having the formula I. The compounds of the invention are selective antagonists of A 2B  adenosine receptors (ARs). These compounds and compositions are useful as pharmaceutical agents for treatment of diseases that are mediated by A 2B  adenosine receptors.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority of U.S. provisional patent applicationsSer. Nos. 60/136,898 filed Jun. 1, 1999, and No. 60/136,900 filed Jun.1, 1999, No. 60/151,875 filed Aug. 31, 1999.

GOVERNMENT FUNDING

The invention described herein was made with government support underGrant Numbers HL37942 and HL56111 awarded by the National Institute ofHealth. The United States Government has certain rights in theinvention.

FIELD OF THE INVENTION

The present invention relates to compounds and pharmaceuticalcompositions that are selective antagonists of A_(2B) adenosinereceptors (ARs). These compounds and compositions are useful aspharmaceutical agents.

BACKGROUND OF THE INVENTION

The alkylxanthine theophylline (compound 1, FIG. 1), a weaknon-selective adenosine antagonist (See Linden, J., et al., inCardiovascular Biology of Purines, eds. G. Burnstock, et al., 1998, pp1-20.) is useful therapeutically for the treatment of asthma. However,its use is associated with unpleasant side effects, such as insomnia anddiuresis. (See Vassallo, R. et al., Mayo. Clin. Proc. 1998, 73,346-354.) In recent years, the use of theophylline as a bronchodilator,for relief of asthma, has been supplanted by drugs of other classes,i.e., selective β₂-adrenergic agonists, corticosteroids, and recentlyleukotriene antagonists. (See Drazen, J. M., et al., New Eng. J. Med.1999, 340, 197-206.) These compounds also have limitations, thus, thedevelopment of a theophylline-like drug with reduced side effects isstill desirable.

It has been recognized that theophylline and its closely relatedanalogue caffeine block endogenous adenosine acting as a local modulatorof adenosine receptors in the brain and other organs at therapeuticallyuseful doses. Adenosine activates four subtypes of G protein-coupledadenosine receptors (ARs), A₁/A_(2A)/A_(2B)/A₃. (See Fredholm, B. B., etal., Pharmacol. Rev. 1999, 51, 83-133.) In comparison to the other knownactions of theophylline, e.g., inhibition of phosphodiesterases,theophylline is more potent in antagonism of adenosine receptors.Enprofylline, (compound 3, FIG. 1) a compound that is used to treatasthma, is another example of a xanthine that has been reported to blockA_(2B) adenosine receptors. However, this compound only weakly blocksA₁, A_(2A) and A₃ adenosine receptors.

It has been reported that therapeutic concentrations of theophylline orenprofylline block human A_(2B) receptors, and it has been proposed thatantagonists selective for this subtype may have potential use asantiasthmatic agents. (See Feoktistov, I., et al., Pharmacol. Rev. 1997,49, 381-402; and Robeva, A. S., et al., Drug Dev. Res. 1996, 39,243-252. Enprofylline has a reported K_(i) value of 7 μM and is somewhatselective in binding to human A_(2B) ARs. (See Robeva, A. S., et al.,Drug Dev. Res. 1996, 39, 243-252 and Linden, J., et al., Mol. Pharmacol.1999, 56, 705-713.) A_(2B) ARs are expressed in some mast cells, such asthe BR line of canine mastocytoma cells, which appear to be responsiblefor triggering acute Ca²⁺ mobilization and degranulation. (SeeAuchampach, J. A., et al., Mol. Pharmacol. 1997. 52, 846-860 andForsyth, P., et al., Inflamm. Res. 1999, 48, 301-307.) A_(2B) ARs alsotrigger Ca²⁺ mobilization, and participate in a delayed IL8 release fromhuman HMC-1 mast cells. Other functions associated with the A_(2B) ARare the control of cell growth and gene expression, (See Neary, J., etal., Trends Neurosci. 1996, 19, 13-18.) endothelial-dependentvasodilation (See Martin, P. L., et al., J. Pharmacol. Exp. Ther. 1993,265, 248-253.), and fluid secretion from intestinal epithelia. (SeeStrohmeier, G. R., et al., J. Biol. Chem. 1995, 270, 2387-2394.)Adenosine acting through A_(2B) ARs has also been reported to stimulatechloride permeability in cells expressing the cystic fibrosis transportregulator. (See Clancy, J. P., et al., Am. J. Physiol. 1999, 276,C361-C369.)

Although adenosine receptor subtype-selective probes are available forthe A₁, A_(2A), and A₃ ARs, only few weakly selective antagonists and noselective agonists are known for the A_(2B) receptor. Therefore, acontinuing need exists for compounds that are selective A_(2B) receptorantagonists.

SUMMARY OF THE INVENTION

The present invention provides compounds that act as antagonists ofA_(2B) adenosine receptors. Accordingly, the present invention providesa compound of formula I:

wherein R, and R¹ are independently hydrogen, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-₈)alkoxy, (C₃-C₈)cycloalkyl,(C₄-C₁₆)cycloalkylalkyl, hetero-cycle, (C₆-C₁₀)aryl, (C₇-C₁₈)aralkyl orheteroaryl;

X is (C₁-C₈)alkylene, (C₂-C₈)alkenylene, (C₂-C₈)alkynylene, wherein oneof the carbon atoms in the alkylene, alkenylene or alkynylene groups canbe replaced with group having the formula —O—, —N(R⁴)C(O)—, —OC(O)—,—N(R⁵)(R⁶)—, —S—, —S(O)— or —SO₂—, wherein

R² is hydrogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₁-C₈)alkoxy, (C₃-C₈)cycloalkyl, (C₃-C₈)heterocycle, (C₆-C₁₀)aryl,(C₆-C₁₀)heteroaryl, (C₄-C₁₆)cycloalkylalkyl or (C₇-C₁₈)aralkyl,optionally substituted with one or more substituents selected from thegroup consisting of —OH, —SH, —NH₂, —NHR⁷, —CN, —CO₂H, and —SO₃H,wherein

R⁴, R⁵, R⁶ and R⁷ are independently hydrogen, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, (C₇-C₁₈)aralkyl orhalo(C₁-C₆)alkyl,

wherein R⁸ is hydrogen, (C₃-C₈)cycloalkyl, (C₄-C₁₆)cycloalkylalkyl,(C₇-C₁₈)aralkyl, heterocycle or heteroaryl, each optionally substitutedwith one or more substituents, wherein the substituents independentlyare oxo, (C₁-C₈)alkyl, halo(C₁-C₆)alkyl, (C₂-C₈)alkenyl, (C₆-C₁₀)aryl,(C₇-C₁₈)aralkyl, heteroaryl, halo, —OR¹⁵, —CN, —NO₂, —CO₂R¹⁵, —OC(O)R¹⁶,—C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴, —C(O)NR¹⁷R¹⁸, —SR¹⁹, —SO₂R²⁰ or—SO₃H; or

R⁸ is (C₁-C₈)alkyl, substituted with one or more substituentsindependently selected from the group consisting of oxo, (C₂-C₈)alkenyl,(C₆-C₁₀)aryl, (C₇-C₁₈)aralkyl, heteroaryl, halo —OR¹⁵, —CN, —NO₂,—CO₂R¹⁵, —OC(O)R¹⁶, —C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴, —C(O)NR¹⁷R¹⁸,—SR¹⁹, —SO₂R²⁰ and —SO₃H; or

R⁸ is (C₆-C₁₀)aryl, substituted with one or more substituentsindependently selected from the group consisting of (C₁-C₈)alkyl,halo(C₁-C₆)alkyl, (C₂-C₈)alkenyl, (C₇-C₁₈)aralkyl, heteroaryl, —OR¹⁵,—CN, —NO₂, —CO₂R¹⁵, —OC(O)R¹⁶, —C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴,—C(O)NR¹⁷R¹⁸, —SR¹⁹, —SO₂R²⁰ and —SO₃H; and

wherein R⁹ is —NR¹⁰R¹¹, or R⁹ is (C₃-C₈)cycloalkyl,(C₄-C₁₆)cycloalkylalkyl, (C₇-C₁₈)aralkyl, heterocycle or heteroaryl,each optionally substituted with one or more substituents, wherein thesubstituents independently are oxo, (C₁-C₈)alkyl, halo(C₁-C₆)alkyl,(C₂-C₈)alkenyl, (C₆-C₁₀)aryl, (C₇-C₁₈)aralkyl, heteroaryl, —OR¹⁵, halo,—CN, —NO₂, —CO₂R¹⁵, —OC(O)R¹⁶, —C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴,—C(O)NR¹⁷R¹⁸, —SR¹⁹, —SO₂R²⁰ or —SO₃H; or

R⁹ is (C₁-₈)alkyl, substituted with one or more substituentsindependently selected from the group consisting of oxo, (C₂-C₈)alkenyl,(C₆-C₁₀)aryl, (C₇-C₁₈)aralkyl, heteroaryl, —OR¹⁵, halo, —CN, —NO₂,—OC(O)R¹⁶, —C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴, —C(O)NR¹⁷R¹⁸, —SR¹⁹,—SO₂R²⁰ and —SO₃H;

R⁹ is (C₆-C₁₀)aryl, substituted with one or more substituentsindependently selected from the group consisting of (C₁-C₈)alkyl,halo(C₁-C₆)alkyl, (C₂-C₈)alkenyl, (C₇-C₁₈)aralkyl, heteroaryl, —OR¹⁵,—CN, —NO₂, —CO₂R¹⁵, —OC(O)R¹⁶, —C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴,—C(O)NR¹⁷R¹⁸, —SR¹⁹, —SO₂R²⁰ and —SO₃H, and

wherein R¹⁰ and R¹¹ are independently hydrogen, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, (C₇-C₁₈)aralkyl,heterocycle, heteroaryl, —C(O)(CH₂)_(n)CO₂R¹²,—C(O)CR²¹═CR²²(CH₂)_(m)CO₂R¹², —C(O)R¹², —C(O)(C₃-C₈)cycloalkyl or—C(O)(C₃-C₈)cycloalkenyl, each optionally substituted with one or moresubstituents, wherein the substituents independently are oxo,(C₁-C₈)alkyl, halo(C₁-C₆)alkyl, (C₂-C₈)alkenyl, (C₆-C₁₀)aryl,(C₇-C₁₈)aralkyl, heteroaryl, —OR¹⁵, halo, —CN, —NO₂, —CO₂R¹⁵, —OC(O)R¹⁶,—C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴, —C(O)NR¹⁷R¹⁸, —SR¹⁹, —SO₂R²⁰ or—SO₃H; or the R¹⁰ and R¹¹ groups and the nitrogen atom can be takentogether to form a heterocyclic ring or a heteroaryl ring, each ringoptionally substituted with one or more substituents, wherein thesubstituents independently are oxo, (C₁-C₈)alkyl, halo(C₁-C₆)alkyl,(C₂-C₈)alkenyl, (C₆-C₁₀)aryl, (C₇-C₁₈)aralkyl, heteroaryl, —OR¹⁵, halo,—CN, —NO₂, CO₂R¹⁵, —OC(O)R¹⁶, —C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴,—C(O)NR¹⁷R¹⁸, —SR¹⁹, —SO₂R²⁰ or —SO₃H; wherein n is 1 to 6, and m is 0to 4;

R¹² is hydrogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₃-C₈)cycloalkyl, (C₄-C₁₆)cycloalkylalkyl, (C₆-C₁₀)aryl,(C₇-C₁₈)aralkyl, hetero-cycle, or heteroaryl,

wherein the R¹² group is optionally substituted with one or moresubstituents independently selected from the group consisting of oxo,(C₁-C₈)alkyl, halo(C₁-C₆)-alkyl, (C₂-C₈)alkenyl, (C₆-C₁₀)aryl,(C₇-C₁₈)aralkyl, heteroaryl, —OR¹⁵, halo, —CN, —NO₂, —CO₂R¹⁵, OC(O)R¹⁶,—C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴, —C(O)NR¹⁷R¹⁸, —SR¹⁹, —SO₂R²⁰ or—SO₃H.

The R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²³ and R²⁴ groups areindependently hydrogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₃-C₈)cycloalkyl,(C₆-C₁₀)aryl, (C₇-C₁₈)aralkyl or halo(C₁-C₆)alkyl; and the R²¹ and R²²groups are independently hydrogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, (C₇-C₁₈)aralkyl.

The invention also provides pharmaceutically acceptable salts of acompound of formula I. The invention also provides a pharmaceuticalcomposition comprising a compound of formula I or a pharmaceuticallyacceptable salt thereof, in combination with a pharmaceuticallyacceptable diluent or carrier.

Additionally, the invention provides a therapeutic method for preventingor treating a pathological condition or symptom in a mammal, such as ahuman, wherein the activity, i.e., over-activity, of adenosine A_(2B)receptors is implicated in one or more symptoms of the pathology andantagonism (i.e., blocking) of their activity is desired to amelioratesaid symptoms. Such diseases or conditions include, but are not limitedto, asthma, diarrheal diseases, insulin resistance, diabetes, preventionof mast cell degranulation associated with ischemia/reperfusioninjuries, inhibition of angiogenesis in neoplastic tissues, andinhibition of angiogenesis in diabetic retinopathy or hyperbaricoxygen-induced retinopathy. The invention also includes a method fortreating asthma, diarrheal diseases, insulin resistance, diabetes,inhibition of angiogenesis in neoplastic tissues, and inhibition ofangiogenesis in diabetic retinopathy or hyperbaric oxygen-inducedretinopathy in a mammal, (e.g., a human) comprising administering to themammal in need of such therapy, an effective amount of at least onecompound of formula I or pharmaceutically acceptable salt(s) thereof.

The invention provides a compound of formula I for use in medicaltherapy preferably for use in treating diseases or conditions associatedwith deleterious A_(2B) receptor activation or activity, includingasthma, diarrheal diseases, insulin resistance, diabetes,ischemic/reperfusion injury, inhibition of angiogenesis in neoplastictissues, and inhibition of angiogenesis in diabetic retinopathy orhyperbaric oxygen-induced retinopathy, as well as the use of a compoundof formula I for the manufacture of a medicament for the treatment of apathological condition or symptom in a mammal, such as a human, which isassociated with deleterious A_(2B) receptor activation or activity,including the above-referenced diseases or pathologies.

The invention also includes a method comprising contacting a compound offormula I, optionally having a radioactive isotope (radionuclide), suchas, for example, tritium, radioactive iodine (for example, ¹²⁵I forbinding assays or ¹²³I for Spect Imaging) and the like, with targetA_(2B) adenosine receptor sites comprising said receptors, in vivo or invitro, so as to bind said receptors. Cell membranes comprising boundA_(2B) adenosine receptor sites can be used to measure the selectivityof test compounds for adenosine receptor subtypes or can be used as atool to identify potential therapeutic agents for the treatment ofdiseases or conditions associated with A_(2B)-receptor mediation, bycontacting said agents with said radioligands and receptors, andmeasuring the extent of displacement of the radioligand and/or bindingof the agent.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates structures of various xanthines that act asantagonists at A_(2B) receptors.

FIG. 2 is a graphic illustration of the inhibition by several selectiveA_(2B) AR antagonists of NECA-stimulated calcium mobilization inHEK-A_(2B) cells. Cells were loaded with Indo 1 for 1 hour. The A)curves indicate calcium mobilization in response to 10 nM and 1 μM NECAadded at the arrow. The B) curves indicate calcium mobilization inresponse to 10 nM NECA added at the arrow in cells pretreated for twominutes with 1% DMSO (control) or with 100 nM of the indicatedantagonists. The results are typical of replicate experiments.

FIG. 3 illustrates the synthesis of amide derivatives of xanthinecarboxylic acid congeners of the invention.

FIG. 4 illustrates the synthesis of hydrazide derivatives of xanthinecarboxylic acid congeners of the invention.

FIG. 5 illustrates the synthesis of hydrazide derivatives of xanthinecarboxylic acid congeners of the invention.

FIG. 6 illustrates the experimental protocol for the ninety minutecardiac left anterior descending (LAD) coronary arteryocclusion/reperfusion test. Regional myocardial blood flow was measuredat 30 second, 90 second, 3 minute, 5 minute, 8 minute, 13 minute, 23minute, 38 minute, and 68 minute, intervals, using radioactivemicrospheres (mic), administered at the times indicated.

FIG. 7 illustrates the regional myocardial transmural blood flow in thecentral infarct (solid bar), border (open bar), and normal (striped bar)zones at baseline, during the LAD occlusion, and 2 hrs afterreperfusion. During the total LAD occlusion, mean flow of test solutionwas <0.2 ml/min/g for 90 min.

FIG. 8 illustrates the mean infarct size measured using triphenyltetrazolium chloride (TTC) staining in vehicle-treated (control) dogsand in dogs treated with8-[4-[((4-cyano)phenylcarbamoylmethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthine(27). The p-cyanoanilide, 27, (200 nm) was infused intracoronary at arate of 1 ml/min during occlusion and reperfusion. The treatmentprevented or markedly attenuate the extent of myocardial infarction andsignificantly reduced the infarct area (IA), measured as % leftventricle area (%LV) or % area at risk (%RA).

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment the present invention provides compounds of formula I:

wherein R, and R¹ are independently hydrogen, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₃-C₈)cycloalkyl,(C₄-C₁₆)cycloalkylalkyl, C₃-C₈)heterocycle, (C₆-C₁₀)aryl,(C₇-C₁₈)aralkyl or (C₆-C₁₀)heteroaryl,

and X is (C₁-C₈)alkylene, (C₂-C₈)alkenylene, (C₂-C₈)alkynylene. In the Xgroups one of the carbon atoms in the alkylene, alkenylene or alkynylenegroups can be replaced with a group having the formula —O—, —N(R⁴)C(O)—,—OC(O)—, —N(R⁵)(R⁶, —S—, —S(O)— or —SO₂—, wherein

R² is hydrogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₁-C₈)alkoxy, (C₃-C₈)cycloalkyl, (C₃-C₈)heterocycle, (C₆-C₁₀)aryl,(C₆-C₁₀)heteroaryl, (C₄-C₁₆)cycloalkylalkyl or (C₇-C₁₈)aralkyl;optionally substituted with one or more substituents selected from thegroup consisting of —OH, —SH, —NH₂, —NHR⁷, —CN, —CO₂H, and —SO₃H,wherein

R⁴, R⁵, R⁶ and R⁷ are independently hydrogen, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, (C₇-C₁₈)aralkyl orhalo(C₁-C₆)alkyl.

R⁸ is hydrogen, (C₃-C₈)cycloalkyl, (C₄-C₁₆)cycloalkylalkyl,(C₇-C₁₈)aralkyl, heterocycle or heteroaryl, each optionally substitutedwith one or more substituents, wherein the substituents independentlyare oxo, (C₁-C₈)alkyl, (C₁-C₈)alkoxy, halo(C₁-C₆)alkyl, (C₂-C₈)alkenyl,(C₆-C₁₀)aryl, (C₇-C₁₈)aralkyl, heteroaryl, halo, —OR¹⁵, —CN, —NO₂,—CO₂R¹⁵, —OC(O)R¹⁶, —C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴, —C(O)NR¹⁷R¹⁸,—SR¹⁹, —SO₂R²⁰ or —SO₃H; or

R⁸ is (C₁-C₈)alkyl, substituted with one or more substituentsindependently selected from the group consisting of oxo, (C₂-C₈)alkenyl,(C₆-C₁₀)aryl, (C₇-C₁₈)aralkyl, heteroaryl, —OR¹⁵, halo, —CN, —NO₂,—OC(O)R¹⁶, —C(O)R¹⁶, —NR¹³R¹⁴, N(R²³)C(O)R²⁴, —C(O)NR¹⁷R¹⁸, —SR¹⁹,—SO₂R²⁰ and —SO₃H; or

R⁸ is (C₆-C₁₀)aryl, substituted with one or more substituentsindependently selected from the group consisting of (C₁-C₈)alkyl,halo(C₁-C₆)alkyl, (C₂-C₈)alkenyl, (C₇-C₁₈)aralkyl, heteroaryl, —OR¹⁵,—CN, —NO₂, —CO₂R¹⁵, —OC(O)R¹⁶, —C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴,—C(O)NR¹⁷R¹⁸, —SR¹⁹, SO₂R²⁰ and —SO₃H; and

wherein R⁹ is (C₃-C₈)cycloalkyl, (C₄-C₁₆)cycloalkylalkyl,(C₇-C₁₈)aralkyl, heterocycle or heteroaryl, each optionally substitutedwith one or more substituents, wherein the substituents independentlyare oxo, (C₁-C₈)alkyl, halo(C₁-C₆)alkyl, (C₂-C₈)alkenyl, (C₆-C₁₀)aryl,(C₇-C₁₈)aralkyl, heteroaryl, —OR¹⁵, halo, —CN, —NO₂, —CO₂R¹⁵, —OC(O)R¹⁶,—C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴, —C(O)NR¹⁷R¹⁸, —SR¹⁹, —SO₂R²⁰ or—SO₃H; or

R⁹ is (C₁-C₈)alkyl, substituted with one or more substituentsindependently selected from the group consisting of oxo, (C₂-C₈)alkenyl,(C₆-C₁₀)aryl, (C₇-C₁₈)aralkyl, heteroaryl, —OR¹⁵, halo, —CN, —NO₂,—OC(O)R¹⁶, —C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴, —C(O)NR¹⁷R¹⁸, —SR¹⁹,—SO₂R²⁰ and —SO₃H; or

R⁹ is (C₆-C₁₀)aryl, substituted with one or more substituentsindependently selected from the group consisting of (C₁-C₈)alkyl,halo(C₁-C₆)alkyl, (C₂-C₈)alkenyl, (C₇-C₁₈)aralkyl, heteroaryl, —OR¹⁵,—CN, —NO₂, —CO₂R¹⁵, —OC(O)R¹⁶, —C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴,—C(O)NR¹⁷R¹⁸, —SR¹⁹, —SO₂R²⁰ and —SO₃H.

The R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²³ and R²⁴ groups areindependently hydrogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₃-C₈)cycloalkyl,(C₆-C₁₀)aryl, (C₇-C₁₈)aralkyl or halo(C₁-C₆)alkyl.

In another embodiment the present invention provides compounds offormula II:

wherein R, and R¹ are independently hydrogen, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-₈)alkoxy, (C₃-C₈)cycloalkyl,(C₄-C₆)cycloalkylalkyl, (C₃-C₈)heterocycle, (C₆-C₁₀)aryl,(C₇-C₁₈)aralkyl or (C₆-C₁₀)heteroaryl,

and X is (C₁-₈)alkylene, (C₂-C₈)alkenylene, (C₂-C₈)alkynylene. In the Xgroups one of the carbon atoms in the alkylene, alkenylene or alkynylenegroups can be replaced with a group having the formula —O—, —N(R⁴)C(O)—,—OC(O)—, —N(R⁵)(R⁶)—, —S—, —S(O)— or —SO₂—, wherein

R² group is hydrogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₁-C₈)alkoxy, (C₃-C₈)cycloalkyl, (C₃-C₈)heterocycle, (C₆-C₁₀)aryl,(C₆-C₁₀)heteroaryl, (C₄-C₁₆)cycloalkylalkyl or (C₇-C₁₈)aralkyl;optionally substituted with one or more substituents selected from thegroup consisting of —OH, —SH, —NH₂, —NHR⁷, —CN, —CO₂H, and —SO₃H,wherein R⁴, R⁵, R⁶ and R⁷ are independently hydrogen, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, (C₇-C₁₈)aralkyl orhalo(C₁-C₆)alkyl.

R⁸ is hydrogen, (C₃-C₈)cycloalkyl, (C₄-C₁₆)cycloalkylalkyl,(C₇-C₁₈)aralkyl, heterocycle or heteroaryl, each optionally substitutedwith one or more substituents, wherein the substituents independentlyare oxo, (C₁-₈)alkyl, (C₁-₈)alkoxy, halo(C₁-C₆)alkyl, (C₂-C₈)alkenyl,(C₆-C₁₀)aryl, (C₇-C₁₈)aralkyl, heteroaryl, halo, —OR¹⁵, —CN, —NO₂,—CO₂R¹⁵, —OC(O)R¹⁶, —C(O)R¹⁶, NR¹³R¹⁴, —N(R²³)C(O)R²⁴, —C(O)NR¹⁷R¹⁸,—SR¹⁹, —SO₂R²⁰ or —SO₃H; or

R⁸ is (C₁-C₈)alkyl, substituted with one or more substituentsindependently selected from the group consisting of oxo, (C₂-C₈)alkenyl,(C₆-C₁₀)aryl, (C₇-C₁₈)aralkyl, heteroaryl, —OR¹⁵, halo, —N, —NO₂,—OC(O)R ¹⁶, —C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴, —C(O)NR¹⁷R¹⁸, —SR¹⁹,—SO₂R²⁰ and —SO₃H; or

R⁸ is (C₆-C₁₀)aryl, substituted with one or more substituentsindependently selected from the group consisting of (C₁-₈)alkyl,halo(C₁-C₆)alkyl, (C₂-C₈)alkenyl, (C₇-C₁₈)aralkyl, heteroaryl, —OR¹⁵,—CN, —NO₂, —CO₂R¹⁵, —OC(O)R¹⁶, —C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴,—C(O)NR¹⁷R¹⁸, —SR¹⁹, —SO₂R²⁰ and —SO₃H; and

wherein R¹⁰ and R¹¹ are independently hydrogen, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, (C₇-C₁₈)aralkyl,heteroaryl, —C(O)(CH₂)_(n)CO₂R¹², —C(O)CR²¹═CR²²(CH₂)_(m)CO₂R¹²,—C(O)R¹², —C(O)(C₃-C₈)cycloalkyl or —C(O)(C₃-C₈)cycloalkenyl, eachoptionally substituted with one or more substituents, wherein thesubstituents independently are oxo, (C₁-C₈)alkyl, halo(C₁-C₆)alkyl,(C₂-C₈)alkenyl, (C₆-C₁₀)aryl, (C₇-C₁₈)aralkyl, heteroaryl, —OR¹⁵, halo,—N, —NO₂, —CO₂R¹⁵, —OC(O)R¹⁶, —C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴,—C(O)NR¹⁷R¹⁸, —SR¹⁹, —SO₂R²⁰ or —SO₃H; or the R¹⁰ and R¹¹ groups and thenitrogen atom can be taken together to form a heterocyclic ring or aheteroaryl ring, each ring optionally substituted with one or moresubstituents, wherein the substituents independently are oxo,(C₁-C₈)alkyl, halo(C₁-₆)alkyl, (C₂-C₈)alkenyl, (C₆-C₁₀)aryl,(C₇-C₁₈)aralkyl, heteroaryl, —OR¹⁵, halo, —CN, —NO₂, CO₂R¹⁵, —OC(O)R¹⁶,—C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴, —C(O)NR¹⁷R¹⁸, —SR¹⁹, —SO₂R²⁰ or—SO₃H; wherein n is 1 to 6, and m is 0 to 4;

R¹² is hydrogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₃-C₈)cycloalkyl, (C₄-C₁₆)cycloalkylalkyl, (C₆-C₁₀)aryl,(C₇-C₁₈)aralkyl, hetero-cycle, or heteroaryl,

wherein the R¹² group is optionally substituted with one or moresubstituents independently selected from the group consisting of oxo,(C₁-C₈)alkyl, halo(C₁-₆)-alkyl, (C₂-C₈)alkenyl, (C₆-C₁₀)aryl,(C₇-C₁₈)aralkyl, heteroaryl, —OR¹⁵, halo, —CN, —NO₂, —CO₂R¹⁵, —OC(O)R¹⁶,—C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴, —C(O)NR¹⁷R¹⁸, —SR¹⁹, —SO₂R²⁰ or—SO₃H.

The R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁸, R¹⁹, R²⁰, R²³ and R²⁴ areindependently hydrogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₃-C₈)cycloalkyl,(C₆-C₁₀)aryl, (C₇-C₁₈)aralkyl or halo(C₁-C₆)alkyl; and the R²¹ and R²²are independently hydrogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, (C₇-C₁₈)aralkyl.

Preferred compounds of the invention exclude compounds of formula Iwherein —NR⁸R⁹ is aminoalkyl, aminodialkyl or hydrazino. Preferredcompounds of the invention also exclude and compounds of formula Iwherein R and R⁸ are both H, and R¹ and R² are both alkyl, and R⁹ is2-hydroxyethyl, 2-thiolethyl, 2-haloethyl, 2,2-dimethoxyethyl,2-acetoxyethyl, 1-methyl-2-phenylethyl, 4-methylphenyl or4-hydroxyphenyl.

Specific and preferred values listed below for radicals, substituents,and ranges, are for illustration only; they do not exclude other definedvalues or other values within defined ranges for the radicals andsubstituents.

The following definitions are used, unless otherwise described: halo isfluoro, chloro, bromo or iodo. Alkyl, alkoxy, alkenyl, alkynyl, etc.denote both straight and branched groups; but reference to an individualradical such as “propyl” embraces only the straight chain radical, abranched chain isomer such as “isopropyl” being specifically referredto. Aryl denotes a phenyl radical or an ortho-fused bicyclic carbocyclicradical having about nine to ten ring atoms in which at least one ringis aromatic.

Heteroaryl encompasses a radical attached via a ring carbon of amonocyclic aromatic ring containing 5-10 ring atoms, and preferably from5-6 ring atoms, consisting of carbon and one to four heteroatoms eachselected from the group consisting of non-peroxide oxygen, sulfur, andN(Y) wherein Y is absent or is H, O, (C₁-₄)alkyl, phenyl or benzyl, aswell as a radical of an ortho-fused bicyclic heterocycle of about eightto ten ring atoms derived therefrom, particularly a benz-derivative orone derived by fusing a propylene, trimethylene or tetramethylenediradical thereto.

The term heterocycle encompasses a cyclic radical attached via a ringcarbon or nitrogen of a monocyclic or bicyclic ring containing 3-10 ringatoms, and preferably from 5-6 ring atoms, consisting of carbon and oneto four heteroatoms each selected from the group consisting ofnon-peroxide oxygen, sulfur, and N(Y) wherein Y is absent or is H, O,(C₁-₄)alkyl, phenyl or benzyl, and optionally containing 1-3 doublebonds (e.g. —CH═CH— or —CH═N—). Heterocycle includes, for example,tetrahydrofuryl, dihydrofuryl, tetrahydroimidazolyl, azanorbomyl,pyrrolidinyl, piperidinyl, piperizinyl, and the like.

Specifically, (C₁-C₈)alkyl can be methyl, ethyl, propyl, isopropyl,butyl, iso-butyl, sec-butyl, pentyl, isopentyl, 3-pentyl, hexyl, heptylor octyl; (C₃-C₈)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl or cyclooctyl; (C₄-C₁₂)cycloalkylalkyl can becyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl,2-cyclopentylethyl or 2-cyclohexylethyl; (C₁-C₈)alkoxy can be methoxy,ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy,3-pentoxy, hexyloxy, heptyloxy or octyloxy; (C₂-C₈)alkenyl can be vinyl,allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,1-pentenyl, 2-pentenyl, 3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl,1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl or4-octenyl; (C₂-C₈)alkynyl can be ethynyl, 1-propynyl, 2-propynyl,1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl,1-hexynyl, 2-hexynyl, 3-hexynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl,1-octynyl, 2-octynyl or 3-octynyl; halo(C₁-C₆)alkyl can be iodomethyl,bromomethyl, chloromethyl, fluoromethyl, trifluoromethyl, 2-chloroethyl,2-fluoroethyl, 2,2,2-tri-fluoroethyl or pentafluoroethyl; (C₆-C₁₀)arylcan be phenyl, indenyl or naphthyl; and heteroaryl can be furyl,imidazolyl, triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl,isothiazoyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, (orits N-oxide), thienyl, pyrimidinyl (or its N-oxide), indolyl,isoquinolyl (or its N-oxide) or quinolyl (or its N-oxide).

The term “amino acid,” comprises the residues of the natural amino acids(e.g., Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Hyl, Hyp, Ile, Leu,Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val) in D or L form, as wellas unnatural amino acids (e.g., phosphoserine, phosphothreonine,phosphotyrosine, hydroxyproline, gamma-carboxyglutamate; hippuric acid,octahydroindole-2-carboxylic acid, statine,1,2,3,4,-tetrahydroisoquinoline-3-carboxylic acid, penicillamine,ornithine, citruline, α-methyl-alanine, para-benzoylphenylalanine,phenylglycine, propargylglycine, sarcosine, and tert-butylglycine). Theterm also comprises natural and unnatural amino acids bearing aconventional amino protecting group (e.g., acetyl, benzyl, COCF₃ orbenzyloxycarbonyl), as well as natural and unnatural amino acidsprotected at the carboxy terminus (e.g., as a (C₁-C₆)alkyl, phenyl orbenzyl ester or amide; or as an a-methylbenzyl amide). Other suitableamino and carboxy protecting groups are known to those skilled in theart (See for example, Greene, T. W.; Wutz, P. G. M. Protecting Groups InOrganic Synthesis, Second Edition, 1991, New York, John Wiley & sons,Inc, and references cited therein). An amino acid can be linked to theremainder of a compound of formula I through the carboxy terminus, theamino terminus or through any other convenient point of attachment, suchas, for example, through the sulfur of cysteine.

The term “peptide” comprises the residues two or more of the naturalamino acids, as well as unnatural amino acids or a mixture thereof, thatare linked through an amide bond. The term also comprises peptides thatare protected at the carboxy terminus (e.g., as a (C₁-C₆)alkyl, phenylor benzyl ester or amide; or as an α-methylbenzyl amide). Other suitableamino and carboxy protecting groups are known to those skilled in theart (See for example, Greene, T. W.; Wutz, P. G. M. Protecting Groups InOrganic Synthesis, Second Edition, 1991, New York, John Wiley & sons,Inc, and references cited therein). A peptide can be linked to theremainder of a compound of formula I through the carboxy terminus, theamino terminus or through any other convenient point of attachment, suchas, for example, through the sulfur of cysteine. Preferably, the peptidehas less than 30 amino acid residues, more preferably less than 20residues, and most preferably from about 2 to about 5 residues.

The preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl,tert-butyl, iso-butyl, and sec-butyl, 1-pentyl, 2-pentyl, 3-pentyl,1-hexyl, 2-hexyl, and 3-hexyl. The preferred alkylene groups aremethylene, ethylene, propylene, butylene, pentylene, and hexylene. Thepreferred alkenyl groups are vinyl, 1-propenyl, 2-propenyl (allyl),1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl,4-pentenyl, 1-hexenyl, 2-hexenyl, and 3-hexenyl. The preferredalkenylene groups are ethenylene, propenylene, butenylene, pentenylene,and hexenylene. The preferred alkynyl groups are ethynyl, 1-propynyl,2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl,3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl,5-hexynyl. The preferred alkoxy groups are methoxy, ethoxy, propoxy,isopropoxy, butoxy, iso-butoxy, and sec-butoxy. The preferred cycloalkylgroups are cyclopentyl, and cyclohexyl. The preferred cycloalkylalkylgroups are, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopentylethyl, and2-cyclohexylethyl. The preferred aryl groups are phenyl, indenyl ornaphthyl. The preferred aralkyl groups are benzyl and 2-phenylethyl. Thepreferred haloalkyl groups are iodomethyl, bromomethyl, chloromethyl,fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or pentafluoroethyl.The preferred heteroaryl groups are furyl, imidazolyl, triazolyl,triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, thiodiazolyl,thiophenyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridinyl, (orits N-oxide), thienyl, pyrimidinyl (or its N-oxide), indolyl,isoquinolyl (or its N-oxide) or quinolyl (or its N-oxide).

A specific Z substituent is:

A specific Z—X moiety is:

Specific R¹ and R² groups are each —CH₂CH₃, —CH₂CH═CH₂, CH₂CH₂CH₃ orcyclohexylmethyl.

Specific R⁸ and R⁹ groups are each hydrogen, substituted phenyl orbenzyl.

Specific R⁴, R⁵, R⁶, and R⁷ groups are each hydrogen, methyl, ethyl,propyl, isopropyl, butyl, vinyl, propenyl, butenyl, cyclopentyl,cyclohexyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl,phenyl and benzyl.

In a preferred embodiment, when the R⁹ groups are phenyl substitutedwith one two or three substituents that are independently cyclopentyl,cyclohexyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl,phenyl, benzyl, —OH, F, Cl, Br, I, —CN, —NO₂, —C(O)OR¹⁵, —C(O)R¹⁶,—NR¹³R¹⁴ or —C(O)NR¹⁷R¹⁸ or benzyl they can optionally be methyl, ethyl,propyl, isopropyl, butyl, vinyl, propenyl, butenyl, cyclopentyl,cyclohexyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl,phenyl, benzyl, —OH, F, Cl, Br, I, —CN, —NO₂, —C(O)OR¹⁵, —C(O)R¹⁶ or—C(O)NR¹⁷R¹⁸, wherein R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷ and R¹⁸ are as definedabove.

The preferred R¹⁰, and R¹¹ groups are hydrogen, methyl, ethyl, propyl,isopropyl, butyl, vinyl, propenyl, butenyl, cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl, trifluoromethyl, 2,2,2-trifluoroethyl,pentafluoroethyl, phenyl and benzyl, —CO(CH₂)_(n)CO₂R¹²,—COCR²¹═CR²²(CH₂)_(m)CO₂R¹², C(O)R¹², —C(O)(C₃-C₈)cycloalkyl,—C(O)(C₃-C₈)cycloalkenyl, and compounds wherein the R¹⁰ and R¹¹ groupsand the nitrogen atom taken together form a ring. More preferred R¹⁰,and R¹¹ groups are independently hydrogen, —CO(CH₂)_(n)CO₂R¹²,—COCR²¹═CR²²(CH₂)_(m)CO₂R¹², —C(O)R¹², —C(O)(C₃-C₆)cycloalkyl and—C(O)(C₃-C₆)cycloalkenyl, each wherein the R¹⁰ and R¹¹ groups and thenitrogen atom taken together form (C₆-C₁₀)heterocycle or(C₆-C₁₀)heteroaryl, n is 1 to 4 and m is 0 to 2. The most preferred R¹⁰,and R¹¹ groups are independently hydrogen, —CO(CH₂)_(n)CO₂R¹²,—COCH═CHCO₂R¹², —C(O)R¹², or wherein the R¹⁰ and R¹¹ groups and thenitrogen atom taken together form a ring or wherein n is 1 to 4 and R¹²,R¹³, R¹⁴, R²¹ and R²² are defined above.

Specific values for —NR⁸R⁹ are:

Specific values for —NR¹⁰R¹¹ are:

The following abbreviations have been used herein:

[¹²⁵I]ABA [¹²⁵I]N⁶-(4-aminobenzyl)-adenosine [¹²⁵I]AB-MECA[¹²⁵I]N⁶-(4-amino-3-iodobenzyl)-adenosine-5′-N- methyluronamide¹²⁵I-ABOPX ¹²⁵I-3-(4-amino-3-iodobenzyl)-8-oxyacetate-1-propyl- xanthine8-SPT 8-sulfophenyltheophylline AR adenosine receptor Bn benzyl BOP-Clbis(2-oxo-3-oxazolidinyl)-phosphinic chloride CGS 216802-[4-[(2-carboxyethyl)phenyl]ethyl-amino]-5′-N- ethylcarbamoyl adenosineCHA N⁶-cyclohexyladenosine CHO cells Chinese hamster ovary cells CPX8-cyclopentyl-1,3-dipropylxanthine DIPEA diisopropylethylamine DMAP4-dimethylaminopyridine DMEM Dulbecco modified eagle medium DMFN,N-dimethylformamide DMSO dimethylsulfoxide EDAC1-ethyl-3-(3-dimethlyaminopropyl)carbodiimide EDTAethylenediaminetetraacetate HEK cells human embryonic kidney cells HOBt1-hydroxybenzotriazole K_(i) equilibrium inhibition constant NECA5I-(N-ethylcarbamoyl)adenosine NHS N-hydroxysuccinimide ester R-PIAR-N⁶-phenylisopropyladenosine SAR structure-activity relationship TFAtrifluoroacetic acid TFAA trifluoroacetic anhydride Tristris(hydroxymethyl)aminomethane XAC8-[4-[[[[(2-aminoethyl)amino]carbonyl]methyl]oxy]phenyl]-1,3-dipropylxanthine XCC8-[4-[[[carboxy]methyl]oxy]phenyl]-1,3- dipropylxanthine ZM 2413854-(2-[7-amino-2-{furyl}{1,2,4}triazolo{2,3-a}{1,3,5}triazin-5-ylaminoethyl)phenol

In cases where compounds are sufficiently basic or acidic to form stablenontoxic acid or base salts, administration of the compounds as saltsmay be appropriate. Examples of pharmaceutically acceptable salts areorganic acid addition salts formed with acids which form a physiologicalacceptable anion, for example, tosylate, methanesulfonate, acetate,citrate, malonate, tartarate, succinate, benzoate, ascorbate,α-ketoglutarate, and α-glycerophosphate. Suitable inorganic salts mayalso be formed, including hydrochloride, sulfate, nitrate, bicarbonate,and carbonate salts.

Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example by reacting a sufficientlybasic compound such as an amine with a suitable acid affording aphysiologically acceptable anion. Alkali metal (for example, sodium,potassium or lithium) or alkaline earth metal (for example calcium)salts of carboxylic acids can also be made.

It will be appreciated by those skilled in the art that compounds of theinvention having a chiral center may exist in and be isolated inoptically active and racemic forms. Some compounds may exhibitpolymorphism. It is to be understood that the present inventionencompasses any racemic, optically-active, polymorphic or stereoisomericform or mixtures thereof, of a compound of the invention, which possessthe useful properties described herein, it being well known in the arthow to prepare optically active forms (for example, by resolution of theracemic form by recrystallization techniques, by synthesis fromoptically-active starting materials, by chiral synthesis or bychromatographic separation using a chiral stationary phase). It is alsoconventional to determine A_(2B) adenosine antagonist activity using thestandard tests described herein or using other similar tests which arewell known in the art.

The compounds of formula I can be formulated as pharmaceuticalcompositions and administered to a mammalian host, such as a humanpatient in a variety of forms adapted to the chosen route ofadministration, i.e., orally or parenterally, by intravenous,intramuscular, topical, inhalation or subcutaneous routes.

Thus, the present compounds may be systemically administered, e.g.,orally, in combination with a pharmaceutically acceptable vehicle suchas an inert diluent or an assimilable edible carrier. They may beenclosed in hard or soft shell gelatin capsules, may be compressed intotablets or may be incorporated directly with the food of the patient'sdiet. For oral therapeutic administration, the active compound may becombined with one or more excipients and used in the form of ingestibletablets, buccal tablets, troches, capsules, elixirs, suspensions,syrups, wafers, and the like. Such compositions and preparations shouldcontain at least 0.1% of active compound. The percentage of thecompositions and preparations may, of course, be varied and mayconveniently be between about 2 to about 60% of the weight of a givenunit dosage form. The amount of active compound in such therapeuticallyuseful compositions is such that an effective dosage level will beobtained.

The tablets, troches, pills, capsules, and the like may also contain thefollowing: binders such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, fructose, lactose or aspartame or a flavoring agent such aspeppermint, oil of wintergreen or cherry flavoring may be added. Whenthe unit dosage form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier, such as a vegetable oilor a polyethylene glycol. Various other materials may be present ascoatings or to otherwise modify the physical form of the solid unitdosage form. For instance, tablets, pills or capsules may be coated withgelatin, wax, shellac or sugar and the like. A syrup or elixir maycontain the active compound, sucrose or fructose as a sweetening agent,methyl and propylparabens as preservatives, a dye and flavoring such ascherry or orange flavor. Of course, any, material used in preparing anyunit dosage form should be pharmaceutically acceptable and substantiallynon-toxic in the amounts employed. In addition, the active compound maybe incorporated into sustained-release preparations and devices.

The active compound may also be administered intravenously orintraperitoneally by infusion or injection. Solutions of the activecompound or its salts can be prepared in water, optionally mixed with anontoxic surfactant. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, triacetin, and mixtures thereof and inoils. Under ordinary conditions of storage and use, these preparationscontain a preservative to prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion caninclude sterile aqueous solutions or dispersions or sterile powderscomprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form should be sterile, fluid and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example, water,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, nontoxic glycerylesters, and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfilter sterilization. In the case of sterile powders for the preparationof sterile injectable solutions, the preferred methods of preparationare vacuum drying and the freeze drying techniques, which yield a powderof the active ingredient plus any additional desired ingredient presentin the previously sterile-filtered solutions.

For topical administration, the present compounds may be applied in pureform, i.e., when they are liquids. However, it will generally bedesirable to administer them to the skin as compositions orformulations, in combination with a dermatologically acceptable carrier,which may be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc, clay,microcrystalline cellulose, silica, alumina and the like. Useful liquidcarriers include water, alcohols or glycols or water-alcohol/glycolblends, in which the present compounds can be dissolved or dispersed ateffective levels, optionally with the aid of non-toxic surfactants.Adjuvants such as fragrances and additional antimicrobial agents can beadded to optimize the properties for a given use. The resultant liquidcompositions can be applied from absorbent pads, used to impregnatebandages and other dressings or sprayed onto the affected area usingpump-type or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts andesters, fatty alcohols, modified celluloses or modified mineralmaterials can also be employed with liquid carriers to form spreadablepastes, gels, ointments, soaps, and the like, for application directlyto the skin of the user.

Examples of useful dermatological compositions which can be used todeliver the compounds of formula I to the skin are known to the art; forexample, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat.No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman(U.S. Pat. No. 4,820,508).

Useful dosages of the compounds of formula I can be determined bycomparing their in vitro activity, and in vivo activity in animalmodels. Methods for the extrapolation of effective dosages in mice, andother animals, to humans are known to the art; for example, see U.S.Pat. No. 4,938,949.

Generally, the concentration of the compound(s) of formula I in a liquidcomposition, such as a lotion, will be from about 0.1-25 wt-%,preferably from about 0.5-10 wt-%. The concentration in a semi-solid orsolid composition such as a gel or a powder will be about 0.1-5 wt-%,preferably about 0.5-2.5 wt-%.

The amount of the compound or an active salt or derivative thereof,required for use in treatment will vary not only with the particularsalt selected but also with the route of administration, the nature ofthe condition being treated and the age and condition of the patient andwill be ultimately at the discretion of the attendant physician orclinician.

In general, however, a suitable dose will be in the range of from about0.5 to about 100 μg/kg, e.g., from about 10 to about 75 μg/kg of bodyweight per day, such as 3 to about 50 μg per kilogram body weight of therecipient per day, preferably in the range of 6 to 90 μg/kg/day, mostpreferably in the range of 15 to 60 μg/kg/day.

The compound is conveniently administered in unit dosage form; forexample, containing 5 to 1000 μg, conveniently 10 to 750 μg, mostconveniently, 50 to 500 μg of active ingredient per unit dosage form.

Ideally, the active ingredient should be administered to achieve peakplasma concentrations of the active compound of from about 0.02, toabout 5 μM, preferably, about 0.05 to 2 μM, most preferably, about 0.1to about 1 μM. This may be achieved, for example, by the intravenousinjection of a 0.005 to 0.5% solution of the active ingredient,optionally in saline or orally administered as a bolus containing about1-100 μg of the active ingredient. Desirable blood levels may bemaintained by continuous infusion to provide about 0.01-0.1 μg/kg/hr orby intermittent infusions containing about 1-10 μg/kg of the activeingredient(s).

The compounds of the invention can be administered by inhalation from aninhaler, insufflator, atomizer or pressurized pack or other means ofdelivering an aerosol spray. Pressurized packs may comprise a suitablepropellant such as carbon dioxide or other suitable gas. In case of apressurized aerosol, the dosage unit may be determined by providing avalue to deliver a metered amount. The inhalers, insufflators, atomizersare fully described in pharmaceutical reference books such asRemington's Pharmaceutical Sciences Volumes 16 (1980) or 18 (1990) MackPublishing Co.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations; such as multiple inhalations from an insufflator or byapplication of a plurality of drops into the eye.

The invention will now be illustrated by the following non-limitingExamples.

EXAMPLES

Pharmacology.

The ability of a compounds of the invention to act as an A_(2B)adenosine receptor antagonists may be determined using pharmacologicalmodels which are well known to the art or using test proceduresdescribed below.

The human A_(2B) receptor cDNA was subcloned into the expression plasmidpDoubleTrouble as described in Robeva, A. et al., Biochem. Pharmacol.,51, 545-555 (1996). The plasmid was amplified in competent JM109 cellsand plasmid DNA isolated using Wizard Megaprep columns (PromegaCorporation, Madison, Wis.). A_(2B) adenosine receptors were introducedinto HEK-293 cells by means of Lipofectin as described in Felgner, P. L.et al., Proc. Natl. Acad. Sci. USA, 84, 7413-7417 (1987).

Cell Culture

Transfected HEK cells were grown under 5% CO₂/95% O₂ humidifiedatmosphere at a temperature of 37° C. Colonies were selected by growthof cells in 0.6 mg/mL G418. Transfected cells were maintained in DMEMsupplemented with Hams F12 nutrient mixture (1/1), 10% newborn calfserum, 2 mM glutamine and containing 50 IU/mL penicillin, 50 mg/mLstreptomycin, and 0.2 mg/mL Geneticin (G418, Boehringer Mannheim). Cellswere cultured in 10 cm diameter round plates and subcultured when grownconfluent (approximately after 72 hours).

Radioligand Binding Studies.

At A_(2B) receptors: COnfluent monolayers of HEK-A_(2B) cells werewashed with PBS followed by ice cold Buffer A (10 mM HEPES, 10 mM EDTA,pH 7.4) with protease inhibitors (10 μg/mL benzamidine, 100 μMphenyhnethanesulfonyl fluoride, and 2 μg/mL of each aprotinin, pepstatinand leupeptin). The cells were homogenized in a Polytron (Brinkmann) for20 s, centrifuged at 30,000×g, and the pellets washed twice with bufferHE (10 mM HEPES, 1 mM EDTA, pH 7.4 with protease inhibitors). The finalpellet was resuspended in buffer HE, supplemented with 10% sucrose andfrozen in aliquots at −80° C. For binding assays membranes were thawedand diluted 5-10 fold with HE to a final protein concentration ofapproximately 1 mg/mL. To determine protein concentrations, membranes,and bovine serum albumin standards were dissolved in 0.2% NaOH/0.01% SDSand protein determined using fluorescamine fluorescence. Stowell, C. P.et al., Anal. Biochem., 572-580 (1978).

Saturation binding assays for human A_(2B) adenosine receptors wereperformed with [³H]ZM214,385 (17 Ci/mmol, Tocris Cookson, Bristol UK)(Ji, X. et al., Drug Design Discov., 16, 216-226 (1999)) or ¹²⁵I-ABOPX(2200 Ci/mmol). To prepare ¹²⁵I-ABOPX, 10 μL of 1 mM ABOPX in methanol/1M NaOH (20:1) was added to 50 μL of 100 mM phosphate buffer, pH 7.3. Oneor 2 mCi of Na¹²⁵I was added, followed by 10 μL of 1 mg/mL chloramine-Tin water. After incubation, 20 minutes at room temperature, 50 μL of 10mg/mL Na-metabisulfite in water was added to quench the reaction. Thereaction mixture was applied to a C18 HPLC column, eluting with amixture of methanol and 5 mM phosphate, pH 6.0. After 5 min at 35%methanol, the methanol concentration was ramped to 100% over 15 min.Unreacted ABOPX eluted in 11-12 minutes; ¹²⁵I-ABOPX eluted at 18-19 minin a yield of 50-60% with respect to the initial ¹²⁵I.

In equilibrium binding assays the ratio of ¹²⁷I/¹²⁵I-ABOPX was 10-20/1.Radioligand binding experiments were performed in triplicate with 20-25μg membrane protein in a total volume of 0.1 mL HE buffer supplementedwith 1 U/mL adenosine deaminase and 5 mM MgCl₂. The incubation time was3 h at 21° C. Nonspecific binding was measured in the presence of 100 μMNECA. Competition experiments were carried out using 0.6 nM ¹²⁵I-ABOPX.Membranes were filtered on Whatman GF/C filters using a Brandel cellharvester (Gaithersburg, Md.) and washed 3 times over 15-20 seconds withice cold buffer (10 mM Tris, 1 mM MgCl₂, pH 7.4). B_(max) and K_(D)values were calculated by Marquardt's nonlinear least squaresinterpolation for single a site binding models. Marquardt, D. M., J.Soc. Indust. Appl. Math., 11, 431-441.21 (1963). K_(i) values fordifferent compounds were derived from IC₅₀ values as described. Linden,J., J. Cycl. Nucl. Res., 8, 163-172 (1982).

Data from replicate experiments are tabulated as means±SEM.

At other Adenosine Receptors: [³H]CPX. Bruns, R. F. et al.,Naunyn-Schmiedeberg's Arch. Pharmacol., 335, 59-63 (1987). ¹²⁵I-ZM241385and ¹²⁵I-ABA were utilized in radioligand binding assays to membranesderived from HEK-293 cells expressing recombinant human A₁, A_(2A) andA₃ ARs, respectively. Binding of [³H]R-N⁶-phenylisopropyladenosine.Schwabe, U. et al., Naunyn-Schmiedeberg's Arch. Pharmacol., 313, 179-187(1980). ([³H]R-PIA, Amersham, Chicago, Ill.) to A₁ receptors from ratcerebral cortical membranes and of [³H]CGS 21680. Jarvis, M. F. et al.,J. Pharmacol. Exp. Therap., 251, 888-893 (1989). (Dupont NEN, Boston,Mass.) to A_(2A) receptors from rat striatal membranes was performed asdescribed. Adenosine deaminase (3 units/mL) was present during thepreparation of the brain membranes, in a pre-incubation of 30 min at 30°C., and during the incubation with the radioligands. All non-radioactivecompounds were initially dissolved in DMSO, and diluted with buffer tothe final concentration, where the amount of DMSO never exceeded 2%.Incubations were terminated by rapid filtration over Whatman GF/Bfilters, using a Brandell cell harvester (Brandell, Gaithersburg, Md.).The tubes were rinsed three times with 3 mL buffer each.

At least six different concentrations of competitor, spanning 3 ordersof magnitude adjusted appropriately for the IC₅₀ of each compound, wereused. IC₅₀ values, calculated with the nonlinear regression methodimplemented in (Graph-Pad Prism, San Diego, Calif.), were converted toapparent K_(i) values as described. Linden, J., J. Cycl. Nucl. Res.,8:163-172 (1982). Hill coefficients of the tested compounds were in therange of 0.8 to 1.1.

Functional Assay:

HEK-A_(2B) cells from one confluent T75 flask were rinsed with Ca²⁺ andMg²⁺-free Dulbecco's phosphate buffered saline (PBS) and then incubatedin Ca²⁺ and Mg²⁺-free HBSS with 0.05% trypsin and 0.53 mM EDTA until thecells detached. The cells were rinsed twice by centrifugation at 250×gin PBS and resuspended in 10 mL of HBSS composed of 137 mM NaCl, 5 mMKCl, 0.9 mM MgSO₄, 1.4 mM CaCl₂, 3 mM NaHCO₃, 0.6 mM Na₂HPO₄, 0.4 mMKH₃PO₄, 5.6 mM glucose, and 10 mM HEPES, pH 7.4 and the Ca²⁺-sensitivefluorescent dye indo-1-AM (5 μM) 37° for 60 min. The cells were rinsedonce and resuspended in 25 mL dye-free HBSS supplemented with 1 U/mladenosine deaminase and held at room temperature. Adenosine receptorantagonists prepared as 100×stocks in DMSO or vehicle was added and thecells and transferred to a 37° bath for 2 minutes. Then the cells (1million in 2 ml) were transferred to a stirred cuvette maintained at 37°within an Aminco SLM 8000 spectrofluorometer (SML instruments, UrbanaIll.). The ratios of indo-1 fluorescence obtained at 400 and 485 nm(excitation, 332 nm) was recorded using a slit width of 4 nm. NECA wasadded after a 100 s equilibration period.

Cyclic AMP Accumulation

Cyclic AMP generation was performed in DMEM/HEPES buffer (DMEMcontaining 50 mM HEPES, pH 7.4, 37° C.). Each well of cells was washedtwice with DMEM/HEPES buffer, and then 100 μL adenosine deaminase (finalconcentration 10 IU/mL) and 100 μL of solutions of rolipram andcilostamide (each at a final concentration of 10 μM) were added,followed by 50 μL of the test compound (appropriate concentration) orbuffer. After 15 minutes, incubation at 37° C. was terminated byremoving the medium and adding 200 μL of 0.1 M HCl. Acid extracts werestored at −20° C. until assay. The amounts of cyclic AMP were determinedfollowing a protocol which utilized a cAMP binding protein (PKA) [vander Wenden et al., 1995], with the following minor modifications. Theassay buffer consisted of 150 mM K₂HPO₄/10 mM EDTA/0.2% BSA FV at pH7.5. Samples (20 mL) were incubated for 90 minutes at 0° C. Incubateswere filtered over GF/C glass microfiber filters in a Brandel M-24 CellHarvester. The filters were additionally rinsed with 4 times 2 mL 150 mMK₂HPO₄/10 mM EDTA (pH 7.5, 4° C.). Punched filters were counted inPackard Emulsifier Safe scintillation fluid after 2 hours of extraction.

The data from the affinity testing for the compounds of the inventionare reported in Tables 1, 2, 3 and 4. The data are reported as Ki in nMor % displacement of specific binding at the designated concentration(where “r” indicates rat cell receptors and “h” indicates human cellreceptors).

The data reported for the A₁ term indicates the level of displacement ofspecific [³H]R-PIA binding in rat brain membranes (rA₁) or recombinanthuman A₁ receptors (hA₁) in HEK 293 cells, expressed as K_(i)±S.E.M.(n=3-5). The data reported for the A_(2A) term is the level ofdisplacement of specific [³H]CGS 21680 binding in rat striatal membranes(rA_(2A)) or recombinant human A_(2A) receptors (hA_(2A)) in HEK 293cells, expressed as K_(i)±S.E.M. (n=3-5). The data reported for theA_(2B) term is the level of displacement of specific [¹²⁵I]ABOPX bindingat human A_(2B) receptors (hA_(2B)) expressed in HEK-293 cells,expressed as K_(i)±S.E.M. (n=3-4). The A₃ term is the level ofdisplacement of specific [¹²⁵I]ABA binding at human A₃ receptors (hA₃)expressed in HEK-293 cells, in membranes, expressed as K_(i)±S.E.M.(n=3-4).

In Table 4 the data reported for the A_(2A) term is the level ofdisplacement of specific [³H]CGS 21680 binding to rat striatal membranes(rA_(2A)) or [¹²⁵I]ABOPX binding to recombinant human A_(2B) receptors(hA_(2B)) in HEK 293 cells, expressed as K_(i)±S.E.M. in μm (n=3-6) oras a percentage of specific binding displaced by a solution of testcompound, at the the designated concentration. In Table 4 the datareported for the hA₃ term is the level of displacement of specific[¹²⁵I]AB-MECA binding at human A₃ receptors expressed in HEK-293 cells,in membranes, expressed as K_(i)±S.E.M. in μM (n=3-4).

TABLE 1 Affinities or antagonistic activities of xanthine derivatives inradioligand binding assays at A₁, A_(2A), A_(2B) and A₃ receptors.

K_(i) or IC₅₀ (nM) Com- hA₁/ hA_(2A)/ hA₃/ pound R¹, R² X R³ rA₁ rA_(2A)hA_(2B) hA₃ hA_(2B) hA_(2B) hA_(2B) 4a n-Pr OCH₂ OH 58 2,200 40 ± 43,910 ± 2,140 4.4 15 98 175 ± 57(h) 595 ± 128(h) 75,700 ± 6,500(r) 4bn-Pr OCH₂ O-Succinimide 153 127 9.75 ± 4.80 227 4c n-Pr OCH₂ NHN- 11.1 ±2.4 126 ± 41 26.6 ± 4.0 670 ± 154 110 74 25 dimethylmaleiyl 3,030 ±1,110(h) 1,970 ± 550(h) 4d n-Pr OCH₂ NH(CH₂)₂NH₂ 1.2 63 7.75 ± 0.14 25.6± 5.0 0.9 2.4 3.3 6.82 ± 1.57(h) 18.4 ± 0.03(h) 5 allyl OCH₂ OH 756 ±147 4,290 ± 570 141 ± 29(h) 816 ± 91 12 17 5.8 1,660 ± 580(h) 2,370 ±290(h) 173,000 ± 18,000(r) 6 n-butyl OCH₂ OH 43.1 ± 9.9 874 ± 107 48.0 ±16.9 90.3 ± 14.2 3.1 53 1.9 149 ± 83(h) 2,540 ± 27,500 ± 1,250(h)2,500(r) 7 Bn OCH₂ OH 679 ± 190 25 ± 3% 1,760 ± 110 (100,000 nM)^(a) 8n-Pr CH═CH OH 15 800 60 ± 2 30 ± 14 2.3 3.2 0.5 140 ± 3(h) 190 ± 71(h)15,000 ± 1,700(r) 9 c-HexylCH₂ CH═CH OH 602 ± 24 <10% 199 ± 52 922 ± 39925 7.6 4.6 (10,000 nM)^(a) 4,890 ± 530(h) 1,518 ± 980(h) 10 Bn CH═CH OH201 ± 23 4,450 ± 1,230 469 ± 23 71 CH—CH═CH₂ OCH₂ NH—Ph(4-CN) 61,200 ±43,000 4,230 ± 340 9.53 ± 1.9 2680 ± 1810 ^(a)% Displacement of specificbinding at the the designated concentration of test compound.

TABLE 2 Affinities or antagonistic activities of xanthine amidederivatives in radioligand binding assays^(a) at A₁, A_(2A), A_(2B) andA₃ receptors.

K_(i) or IC₅₀ (nM) Com- hA₃/ hA₁/ hA_(2A)/ pound R³ rA₁ rA_(2A) hA₁hA_(2A) hA_(2B) hA₃ hA_(2B) hA_(2B) hA_(2B) 11 NH₂ 20.0 ± 3.8 76.3 ±14.0 16.3 ± 4.2 12 NH—Ph 4.22 ± 0.88 45.6 ± 1.4 40.1 ± 5.1 25.8 ± 4.51.48 ± 0.63 137 ± 54 27 17 93 13 NH—CH₂Ph 5.02 ± 0.55 25.9 ± 7.6 54.7 ±21.2 23.8 ± 5.71 2.04 ± 0.17 79.2 ± 17.8 27 12 39 14 NH—CH(Ph)₂ 120 ± 2120 ± 8% 33.7 ± 17.0 (1000)^(b) 15 N(CH₂Ph)₂ 167 ± 49 2,750 ± 800 690 ±98 642 ± 198 9.88 ± 1.05 284 ± 14 70 65 29 16 N(CH₃)Ph 218 ± 80 497 ±250 5.42 ± 1.71 17 N(CH₂COOEt)₂ 26.8 ± 2.4 999 ± 144 43.4 ± 8.4 18NH—Ph-(2- 27.9 ± 1.6 434 ± 129 335 ± 64 431 ± 176 2.74 ± 1.01 61.9 ± 3.4120 160 23 COCH₃) 19 NH—Ph-(3- 439 ± 111 949 ± 394 234 ± 28 58.9 ± 7.14.92 ± 0.55 352 ± 69 48 12 72 COCH₃) 20 NH—Ph-(4- 37.6 ± 4.0 548 ± 183157 ± 8 112 ± 37 1.39 ± 0.30 230 ± 23 110 81 170 COCH₃) 21 NH—Ph-(4-38.4 ± 3.9 541 ± 128 225 ± 9 3,100 ± 1540 3.93 ± 1.35 363 ± 148 57 79092 COOCH₃) 22 NH—Ph-(4- 10.2 ± 2.5 683 ± 167 7.75 ± 1.11 CONH₂) 23NH—Ph-(4- 24.8 ± 1.8 98.1 ± 49.6 3.34 ± 0.51 CONHCH₃) 24 NH—Ph-(4- 145 ±28 220 ± 79 16.1 ± 4.7 COOH) 25 NH—Ph-(4-CH₃) 17.5 ± 5.0 126 ± 38 1.88 ±0.76 26 NH—Ph-(4-OH) 5.88 ± 1.06 63.3 ± 20.4 3.71 ± 0.76 27 NH—Ph-(4-CN)16.8 ± 3.6 612 ± 287 403 ± 194 503 ± 10.8 1.97 ± 0.31 570 ± 184 210 260290 28 NH—Ph-(4-NO₂) 13.1 ± 3.9 1,180 ± 360 57.0 ± 3.1 70.0 ± 10.7 1.52± 0.24 138 ± 17.1 38 46 91 29 NH—Ph-(4-CF₃) 44.6 ± 6.5 917 ± 258 61.2 ±8.2 238 ± 28 2.14 ± 0.47 213 ± 94 29 110 100 30 NH—Ph-(4-F) 2.72 ± 0.51988 ± 518 17.9 ± 4.5 16.6 ± 3.6 2.22 ± 0.19 391 ± 147 8.1 7.5 176 31NH—Ph-(4-Cl) 6.35 ± 1.47 995 ± 550 49.7 ± 14.2 187 ± 38 2.47 ± 0.711,870 ± 370 20 400 760 32 NH—Ph-(4-Br) 7.46 ± 2.66 221 ± 36 73.5 ± 23.31,640 ± 660 2.35 ± 0.01 2,300 ± 420 31 700 980 33 NH—Ph-(4-I) 15.7 ± 4.2152 ± 47 293 ± 67 5,140 ± 540 2.13 ± 0.12 1,270 ± 130 140 2,400 600^(a)The methods of each binding assay are described above.

TABLE 3 Affinities or antagonistic activities of miscellaneous xanthinederivatives in radioligand binding assays^(a) at A₁, A_(2A), A_(2B) andA₃ receptors.

K_(i) or IC₅₀ (nM) Compound R¹, R² X R³ rA₁ rA_(2A) hA_(2B) hA₃ 34 n-PrCH═CH NHN-dimethylmalelyl 3.94 ± 1.20 406 ± 105 16.7 ± 3.0 31.0 ± 3.1105 ± 5(h) 223 ± 55(h) 35 n-Pr CH═CH NH—Ph-(2-COCH₃) 7.67 ± 2.20 143 ±50 3.65 ± 0.98 121 ± 138 36 c- CH═CH NH—Ph-(2-COCH₃) (10,000 nM)^(b)(10,000 nM)^(b) (10,000 nM)^(b) HexMe 37 Bn CH═CH NH—Ph-(2-COCH₃) 34,300(10,000 nM)^(b) (10,000 nM)^(b) 38 Bn OCH₂ NH—Ph-(2-COCH₃) (10,000nM)^(b) (10,000 nM)^(b) (10,000 nM)^(b) 39 Et OCH₂ NH—Ph-(4-CH₃) 34.9 ±0.3 71.1 ± 7.7 1.78 ± 0.43 (1000 nM)^(b) 40 Et OCH₂ NH—Ph- 65.0 ± 15.41370 ± 490 15.2 ± 6.8 (4-CH₂CONH— (CH₂)₂NH₂) ^(a)The methods of eachbinding assay are as described above. ^(b)<10% displacement of specificbinding at the the designated concentration of test compound.

TABLE 4 Affinities of xanthine derivatives in radioligand bindingassays^(b) at rat A₁, rat A_(2A), human A_(2B), and human A₃ receptors,unless noted^(a).

Ki (nM) or % displacement Compound R⁹ R¹ rA₁ rA_(2A) hA_(2B) hA₃rA₁/hA_(2B) 4e — Pr 51.6 ± 8.0, 128 ± 15, 18.7 ± 0.5, 48.5 ± 0.8^(a) 2.8230 ± 59(h)^(a) 342 ± 10(h)^(a) 34.5 ± 6.3^(a) 4f —NH₂ Pr 16.0 ± 0.563.8 ± 21.3 13.2 ± 5.9 498 ± 139 1.2 4l —NH—COCH₃ Pr 6.51 ± 1.24, 227 ±64, 65.4 ± 6.5, 30.9 ± 8.2^(a) 0.10 125 ± 14(h)^(a) 186 ± 9(h)^(a) 33.8± 13.7^(a) 42

Pr 73.3 ± 22.0, 219 ± 3(h)^(a) 174 ± 32, 795 ± 98(h)^(a) 116 ± 10, 97.8± 3.3^(a) 173 ± 27 1.6 43

Pr 55.9 ± 25.1 75.2 ± 5.5(h)^(a) 805 ± 44 27.2 ± 8.6(h)^(a) 18.6 ± 6.1766 ± 176 3.0 44

Pr 74.3 ± 6.6 139 ± 32 30.2 ± 0.5 1560 2.5 45

Pr 3.87 ± 1.20 21.4 ± 6.1 3.86 ± 0.7 151 ± 99 1.0 46

Pr 203 ± 41 1230 ± 270 144 ± 11 551 ± 106 1.4 47

Pr 11.1 ± 2.4, 3030 ± 1110(h)^(a) 126 ± 41, 1970 ± 550(h)^(a) 19.4 ±6.2, 33.8 ± 1.9^(a) 670 ± 154^(a) 0.57 48

H 3590 ± 920, 8080 ± 720(h)^(a) 36 ± 4% (100,000 nM)^(c), 5480 ±920(h)^(a) 1800 ± 0, 1900 ± 280^(a) 14,200 ± 11,500^(a) 2.0 49

Pr 225 ± 76 1540 ± 280 66.7 ± 37.0 748 ± 234 3.4 50

Pr 95.8 ± 25.1 2100 ± 630 27.9 ± 8.5 3450 ± 1470 3.4 51

Pr 134 ± 19 813 ± 299 51.0 ± 7.0 1060 ± 150 2.6 52

Pr 36.4 ± 6.2 129 ± 20(h)^(a) 689 ± 477 301 ± 31(h)^(a) 10.0 ± 3.0 370 ±190 3.6 53

Pr 81.7 ± 31.2 708 ± 169 78.5 ± 20.5 1180 ± 700 1.0 54

Pr 41.3 ± 6.4 1160 ± 337 21.5 ± 1.5 309 ± 88 1.9 55

Pr 47.2 ± 6.8 145 ± 11(h)^(a) 422 ± 136 95.6 ± 16.8(h)^(a) 17.3 ± 6.3438 ± 109 2.7 56

Pr 61.9 ± 11.3 415 ± 157 35.8 ± 0.7 245 ± 45 1.7 57

Pr 26.3 ± 2.3, 210 ± 42(h)^(a) 392 ± 117, 359 ± 21(h)^(a) 64.4 ± 0.8,46.4 ± 14.5^(a) 147 ± 21^(a) 0.41 58

Pr 14.0 ± 2.3 135 ± 39 22.0 ± 5.5 200 ± 45 0.6 59

Pr 41.2 ± 16.6 164 ± 61 25.7 ± 5.5 290 ± 88 1.6 60

Pr 70.8 ± 30.9 872 ± 412 24.8 ± 7.3 430 ± 44 2.9 61

Pr 53.5 ± 6.5 149 ± 6(h)^(a) 440 ± 106 178 ± 20(h)^(a) 13.0 ± 3.5 726 ±245 4.1 62

Pr 197 ± 67 2750 ± 950 47.5 ± 2.5 195 ± 84 4.1 63

Pr 113 ± 27 524 ± 285 39.7 ± 13.6 690 ± 570 2.8 64 Cbz-(Gly)₂-NH— Pr36.0 ± 6.6 609 ± 95 10.8 ± 5.0 323 ± 47 3.3 200 ± 22(h)^(a) 830 ±84(h)^(a) ^(a)K_(i) values were determined in radioligand binding assaysat recombinant human A₁ and A_(2A) receptors expressed in HEK-293 cellsvs [³H]CPX and [¹²⁵I]ZM241385, respectively. Affinity of xanthinederivatives at human A_(2B) receptors expressed in HEK-293 cells wasdetermined using [¹²⁵I]-ABOPX. Affinity at recombinant human A₃receptors expressed in HEK-293 cells was determined using [¹²⁵I]ABA.^(b)The methods of each binding assay are as described above. ^(c)%Displacement of specific binding at the the designated concentration oftest compound.

The potency of the xanthine derivatives at human A_(2B) receptors wasevaluated using two binding assays. Tables 1, 2 and 3 illustrate theresults from the anilide compounds. Table 4 illustrates the results fromthe hydrazide compounds. FIG. 2 shows functional inhibiton by anilidecompounds. The K_(i) values of the xanthine derivatives were determinedin displacement of binding of two non-selective radioligands4-(2-[7-amino-2-{furyl}{1,2,4}triazolo{2,3-a}{1,3,5}triazin-5-ylaminoethyl)-phenol([³H]ZM241385), and¹²⁵I-3-(4-amino-3-iodobenzyl)-8-phenyloxyacetate-1-propyl-xanthine(¹²⁵I-ABOPX), at human A_(2B) receptors stably expressed in HEK-293 cellmembranes. The results obtained with these two radioligands were nearlyidentical. In order to determine selectivity, the xanthines wereevaluated using standard binding assays at A₁, A_(2A), and A₃ receptors.The initial screening utilized rat brain A₁/A_(2A) receptors (withradioligands [³H]R-PIA and [³H]CGS21680), and selected compounds wereexamined at the recombinant human subtypes, using[³H]8-cyclopentyl-1,3-dipropylxanthine ([³H]CPX) (A₁, See Bruns, R. F.,et al., Naunyn-Schmiedeberg's Arch. Pharmacol. 1987, 335, 59-63.) and¹²⁵I-4-(2-[7-amino-2-[2-furyl]-[1,2,4]triazolo[2,3-α][1,3,5]-triazin-5-yl-amino]-ethyl)phenol(¹²⁵I-ZM241385) (A₂). Affinity at cloned human A₃ receptors expressed inHEK-293 cells was determined usingN⁶-(4-amino-3-[¹²⁵I]iodobenzyl)-adenosine (¹²⁵I-ABA) orN⁶-(4-amino-3-iodobenzyl)-adenosine-5′-N-methyluronamide (¹²⁵I-AB-MECA).

The 8-(4-Phenylacrylic) acid derivatives, 8-10, tended to be more potentat A₁ receptors and less potent at A_(2B) receptors than the8-(4-carboxymethyloxy-phenyl) derivatives. The 1,3-dicyclohexylmethylderivative, 9, for example, was more selective for A_(2B) receptors. Aprimary carboxamide, 11, was more potent than the carboxylic acid, 4a,at A₁ (3-fold) and A_(2A) (29-fold) receptors, and equipotent at A_(2B)receptors.

The adenosine receptor affinities of aryl, compounds 12 and 18-33,alkyl, compound 17, and aralkyl, compounds 13-16, amides of 4a werecompared. A benzyl amide, compound 13, and simple anilides had thehighest affinity of binding, in the nanomolar range, to human A_(2B)receptors. Selectivities for the human A_(2B) versus rat A₁ receptorsranged from 1-(compound 30) to 27-(compound 20) fold, while comparisonswithin the same species (human) generally led to greater selectivities.Anilides substituted in the p-position with groups such as nitro, cyano,and acetyl, displayed the highest selectivity. An N-methyl anilide of4a, compound 16, was 40- and 92-fold selective for human A_(2B)receptors versus rat A₁/A_(2A) receptors, thus the N-methylation reducedaffinity by 3.7-fold but increased selectivity. An o-substitutedacetophenone, compound 18 was 120-, 160-, and 23-fold selective forhuman A_(2B) receptors versus human A₁/A_(2A)/A₃ receptors and 10-, and160-fold selective versus rat A₁/A_(2A) receptors. The p-substitutedacetophenone, compound 20, was more potent at A_(2B) receptors than thecorresponding o- and m-isomers. Other highly potent and moderatelyselective A_(2B) antagonists were a p-trifluoromethyl derivative,compound 29 (K_(i) value 2.14 nM), and a p-cyanoanilide, compound 27(K_(i) value 1.97 nM), which was highly selective versus the other humansubtypes, but only 8.5-fold selective versus rat A₁ receptors. Thep-cyanoanilide, 27, was tritiated on the 1,3-dipropyl groups and servesas a selective radio ligand for A_(2B) receptors. A p-nitro derivative,compound 28, bound to human A_(2B) receptors with a K_(i) of 1.52 nM butwas only 35-fold selective versus human A₁ receptors. A p-iododerivative, compound 33 (K_(i) value 2.13 nM), was 140-, 2400-, and600-fold selective for human A_(2B) receptors versus human A₁/A_(2A)/A₃receptors. Substitution of the 1,3-dipropyl groups with ethyl, as incompounds 40 and 41, offered no disadvantage for selectivity, but highaffinities were maintained.

The functional effects of several selective A_(2B) antagonists ininhibiting the effects of NECA in HEK-A_(2B) cells were examined (FIG.2). Several selective A_(2B) adenosine receptor antagonists at 100 nMnearly completely inhibited NECA-stimulated calcium mobilization. Incomparison, XAC(8-[4-[[[[(2-aminoethyl)amino]carbonyl]methyl]oxy]phenyl]-1,3-dipropylxanthine),which has a K_(i) value of 12.3 nM in binding to human A_(2B), (See deZwart, M.; et al., Nucleos. Nucleot. 1998, 17, 969-986.) inhibited theNECA-stimulated calcium mobilization effect by about half. Thus, thepotency of the xanthines in the functional assay was parallel to resultsfrom the binding assay. The 1,2-dimethylmaleimide derivative, 47, boundto human A_(2B), receptors with a K_(i) of 19 nM and proved to beselective vs. human A₁/A_(2A)/A₃ receptors by 160-, 100-, and 35-fold,respectively Other potent and selective A_(2B) antagonists were atetrahydrophthaloyl derivative 52 (K_(i) value 10 nM) and amino acidconjugates of the XCC-hydrazide, i.e., the glutarimide 61 (K_(i) value13 nM) and protected dipeptide 64 (K_(i) value 11 nM). Compound 55displayed a K_(i) value of 17 nM. Other derivatives displayingselectivity for A_(2B) receptors, but with less potency (K_(i) values innM) were compounds: 44 (30), 49 (67), 50 (28), 60 (25), 62 (48), and 63(40).

Synthesis and Characterization

Compounds 4a, 4b, 4c, 11, 25, and 26 were synthesized as reported inJacobson, et al., J. Med. Chem. 1985, 28, 1334-1340. Compound 5, 6, 7and 10 were synthesized as reported in Kim, H. O.; et al., J. Med. Chem.1994, 37, 3373-3382. Compound 39 and 40 were synthesized as reported inJacobson, K. A et al., J. Med. Chem. 1987, 30, 211-214. R-PIA, NECA,XAC, and 2-chloroadenosine were purchased from Research BiochemicalsInternational (Natick, Mass.). All other agents were purchased fromAldrich (St. Louis, Mo.).

Proton nuclear magnetic resonance spectroscopy was performed on a VarianGEMINI-300 spectrometer and spectra were taken in DMSO-d₆ or CDCl₃.Unless noted, chemical shifts are expressed as ppm downfield fromtetramethylsilane or relative ppm from DMSO (2.5 ppm).Chemical-ionization (CI) mass spectrometry was performed with a Finnigan4600 mass spectrometer, and Electron-impact (EI) mass spectrometry witha VG7070F mass spectrometer at 6 kV for high resolution mass. FAB (fastatom bombardment) mass spectrometry was performed with a JEOL SX102spectrometer using 6-kV Xe atoms.

Elemental analysis (±0.4% acceptable) was performed by Atlantic MicrolabInc. (Norcross, Ga.). All melting points were determined with a Unimeltcapillary melting point apparatus (Arthur H. Thomas Co., PA) and wereuncorrected. All xanthine derivatives were homogeneous as judged usingTLC (MK6F silica, 0.25 mm, glass backed, Whatman Inc., Clifton, N.J.).All xanthine derivatives tested in binding assays were shown to behomogeneous by TLC (MK6F silica, 0.25 mm, glass backed, Whatman Inc.,Clifton, N.J.). NMR and mass spectra were shown to be consistent withthe assigned structure.

Example 1 General Procedure for the Preparation of Amide Derivatives of8-[4-[[[Carboxyl]methyl]oxy]phenyl]-1,3-dipropylxanthine Analogs 4a,7-10 (Collectively “XCC”)

Method A (Carbodiimide)

A solution of XCC (0.0517 mmole), the desired amine compound (0.103mmole), EDAC (20 mg, 0.103 mmole), and DMAP (4 mg, 0.032 mmole) in 2 mLof anhydrous DMF/CH₂Cl₂ (1:1 v/v) was stirred at room temperature for 24hours. The mixture was evaporated to dryness under reduced pressure. Theresidue was purified by preparative silica gel TLC (CHCl₃:MeOH=20:1) andcrystallization in MeOH/ether or MeOH/CH₂Cl₂ to afford the desiredcompounds (12-14, 18, 36).

Method B (BOP-Cl)

A solution of XCC (0.0517 mmole), the desired amine compound (0.103mmole), BOP-Cl (14 mg, 0.0517 mmole), and triethylamine (20 μl, 0.206mmole) in 2 mL of anhydrous CH₂Cl₂ was stirred at room temperature for24 hours. The mixture was treated according to the same procedure asMethod A for purification of the desired compounds. (15, 17, 19, 20, 38)

Method C (Acid Chloride)

A solution of XCC (0.0517 mmole) in 1 mL of thionyl chloride was stirredat 70° C. for 4 hours. The excess thionyl chloride was removed with anitrogen stream. To the residue was added a solution of the desiredamine compound (0.103 mmole) in 1 mL of anhydrous pyridine and 1 mL ofanhydrous CH₂Cl₂. The mixture was stirred at room temperature for 24hours. The mixture was subjected to the same procedure as described inMethod A for purification of the desired compounds. (16, 21, 22, 27-35,37)

Example 2 General Procedure for the Preparation of Xanthine HydrazideDerivatives

The hydrazide of XCC, 4f, was acylated with a variety of mono- anddicarboxylic acids. Cyclization reactions were carried out fordicarboxylic acids, in two steps using an anhydride, (compound 72, FIG.4), for acylation, leading to imide (5- or 6-membered ring) derivatives.The final step of ring-closure of 73 to 74 was effected at 50° C., usingexcess carbodiimide and 1-hydroxybenzo-triazole as catalyst. In somecases, where symmetric dicarboxylic acids were used, it was possible toisolate both the open structure, 73, and the cyclized imide form, 74.Pairs of open and cyclized derivatives of symmetric dicarboxylic acidsprepared include compounds 51-56. Also, the glutamic acid derivative 60,was prepared using orthogonal protecting and the corresponding imide,61. An 8-phenyl analogue, 48, of enprofylline was synthesized bystandard methods from the asymmetric urea, (FIG. 5).

A. Carboxyalkyl Amide Derivatives

A mixture of compound 4f (10 mg, 0.025 mmol), and 2 equivalents ofanhydride were stirred in 1 mL of DMF for 6-24 hours. The reactionmixture was concentrated to dryness, and the residue was purified onpreparative TLC (CHCl₃:MeOH=10:1) to afford the correspondingcarboxyalkylamide derivative as a white solid with 40-70% yield.(compounds 41, 42, 51, 53, 55)

B. Cyclic Imide Derivatives

A mixture of compound 4f (10 mg, 0.025 mmol), 1.5-2.0 equivalents ofanhydride and 1 equivalent of DIPEA were stirred in 1 mL of DMF at roomtemperature. When the starting material 4f disappeared, as judged byTLC, a mixture of 2-3 equivalents of HOBt, EDAC, and DIPEA, dissolved in0.5 mL of DMF, was added. The mixture was stirred at room temperature orat 50° C. for 6-24 hours. The reaction mixture was concentrated todryness, and the residue was purified on preparative TLC(CHCl₃:MeOH=10:1) to afford the cyclic imide derivative as a whitesolid, 40-70% yield. (compounds 43, 44, 45, 46, 47, 48, 49, 50, 52, 54,56, 57, 58, and 59)

C. Coupling with Activated N-protected Amino Acids

A mixture of compound 4f (10 mg, 0.025 mmol), 1.5-2.0 equivalents ofactivated (hydroxy-succinimide or 4-nitrophenyl ester) N-protected aminoacid and 1 equivalent of DIPEA and DMAP, in 1 mL of DMF, was stirred at25-50° C. for 8-24 hours. The reaction mixture was concentrated todryness. The residue was purified by preparative TLC (CHCl₃:MeOH=10: 1)to afford the product as a white solid, 40-70% yield. (compounds 62, 63and 64)

Example 3 8-[4-[(Carboxymethyl)oxy]phenyl]-1,3-dibenzyl-xanthine (7)

¹H NMR (DMSO-d₆) 4.23 (s, 2H, —OCH₂—), 5.10 (s, 2H, —NCH₂—), 5.23 (s,2H, —NCH₂—), 6.88 (d, 2H, J=8.8 Hz, Ar), 7.22-7.41 (m, 10H, 2×-Ph), 8.01(d, 2H, J=8.8 Hz, Ar).

Example 4 8-(4-(2-Carboxy-trans-vinyl)phenyl)-1,3-dibenzyl-xanthine (10)

¹H NMR (DMSO-d₆) 5.12 (s, 2H, —NCH₂—), 5.26 (s, 2H, —NCH₂—), 6.63 (d,1H, J=15.6 Hz, —CH═), 7.22-7.43 (m, 10H, 2×-Ph), 7.63 (d, 1H, J=15.6 Hz,—CH═), 7.84 (d, 2H, J=8.8 Hz, Ar), 8.17 (d, 2H, J=8.8 Hz, Ar).

Example 58-[4-[(Phenylcarbamoylmethyl)oxy]phenyl]-1,3-di-(n-propyl)-xanthine (12)

¹H NMR (DMSO-d₆). 0.89 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.58 and 1.74 (2m,4H, 2×—CH₂—), 3.87 and 4.02 (2t, 4H, J=6.8 Hz, 2×—NCH₂—), 4.80 (s,2_(H, —OCH) ₂—), 7.06-7.12 (m, 1H, -Ph), 7.14 (d, 2H, J=8.8 Hz, Ar),7.33 (t, 2H, J=7.8 Hz, -Ph), 7.64 (d, 2H, J=7.8 Hz, -Ph), 8.09 (d, 2H,J=8.8 Hz, Ar), 10.13 (s, 1H, —NH).

Example 68-[4-[(Benzylcarbamoylmethyl)oxy]phenyl]-1,3-di-(n-propyl)-xanthine (13)

¹H NMR (DMSO-d₆). 0.89 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.58 and 1.74 (2m,4H, 2×—CH₂—), 3.87 and 4.02 (2t, 4H, J=6.8 Hz, 2×—NCH₂—), 4.36 (d, 2H,J=5.9 Hz, —NH—CH ₂—), 4.80 (s, 2H, —OCH₂—), 7.12 (d, 2H, J=8.8 Hz, Ar),7.22-7.34 (m, 5H, -Ph), 8.08 (d, 2H, J=8.8 Hz, Ar), 8.70 (t, 1H, J=5.9Hz, —NH—).

Example 78-[4-[(Diphenylmethylcarbamoylmethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthine(14)

¹H NMR (DMSO-d₆). 0.89 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.58 and 1.74 (2m,4H, 2×—CH₂—), 3.87 and 4.02 (2t, 4H, J=6.8 Hz, 2×—NCH₂—), 4.73 (s, 2H,—OCH₂—), 6.20 (d, 1H, J=8.8 Hz, —NH—CH ₂—), 7.08 (d, 2H, J=8.8 Hz, Ar),7.23-7.37 (m, 10H, 2×-Ph), 8.07 (d, 2H, J=8.8 Hz, Ar), 9.06 (d, 1H,J=8.8 Hz, —NH—).

Example 88-[4-[(Dibenzylcarbamoylmethyl)oxy]phenyl]-1,3-di-(n-propyl)-xanthine(15)

¹H NMR (DMSO-d₆). 0.89 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.58 and 1.74 (2m,4H, 2×—CH₂—), 3.87 and 4.02 (2t, 4H, J=6.8 Hz, 2×—NCH₂—), 4.52 (s, 2H,—NCH₂—), 4.59 (s, 2H, —NCH₂—), 5.03 (s, 2H, —OCH₂—), 6.99 (d, 2H, J=8.8Hz, Ar), 7.22-7.44 (m, 10H, 2×-Ph), 8.05 (d, 2H, J=8.8 Hz, Ar).

Example 98-[4-[(N-Methyl-N-phenylcarbamoylmethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthine(16)

¹H NMR (DMSO-d₆). 0.89 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.58 and 1.74 (2m,4H, 2×—CH₂—), 3.22 (s, 3H, —NCH₃), 3.88 and 4.01 (2t, 4H, J=6.8 Hz,2×—NCH₂—), 4.54 (s, 2H, —OCH₂—), 6.91 (bs, 2H, Ar), 7.30-7.55 (m, 5H,-Ph), 8.03 (d, 2H, J=8.8 Hz, Ar).

Example 108-[4-[(N,N-bis(Ethoxycarbonylmethyl)carbamoylmethyl)oxy]-phenyl]-1,3-di-(n-propyl)xanthine(17)

¹H NMR (DMSO-d₆). 0.89 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.20 (2t, 6H, J=6.8Hz, 2×—CH₃), 1.58 and 1.74 (2m, 4H, 2×—CH₂—), 3.87 and 4.02 (2t, 4H,J=6.8 Hz, 2×—NCH₂—), 4.06-4.20 (m, 4H, —OCH₂—), 4.11 (s, 2H, —NCH₂—),4.38 (s, 2H, —NCH₂—), 4.94 (s, 2H, —OCH₂—), 7.00 (d, 2H, J=8.8 Hz, Ar),8.05 (d, 2H, J=8.8 Hz, Ar).

Example 118-[4-[((2-Acetylphenyl)carbamoylmethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthine(18)

¹H NMR (DMSO-d₆). 0.89 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.59 and 1.74 (2m,4H, 2×—CH₂—), 3.87 and 4.02 (2t, 4H, J=6.8 Hz, 2×—NCH₂—), 4.70 (s, 3H,—COCH₃), 4.72 (s, 2H, —OCH₂—), 7.15 (d, 2H, J=8.8 Hz, Ar), 7.56 (t, 1H,J=6.8 Hz, Ar), 7.69 (t, 1H, J=6.8 Hz, Ar), 8.02 (d, 2H, J=6.8 Hz, Ar),8.11 (d, 2H, J=8.8 Hz, Ar), 8.48 (m, 1H, —NH—).

Example 128-[4-[((3-Acetylphenyl)carbamoylmethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthine(19)

¹H NMR (DMSO-d₆). 0.89 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.59 and 1.74 (2m,4H, 2×—CH₂—), 2.57 (s, 3H, —COCH₃), 3.87 and 4.02 (2t, 4H, J=6.8 Hz,2×—NCH₂—), 4.82 (s, 2H, —OCH₂—), 7.16 (d, 2H, J=8.8 Hz, Ar), 7.50 (t,1H, J=7.8 Hz, Ar), 7.71 (d, 1H, J=7.8 Hz, Ar), 7.92 (d, 1H, J=7.8 Hz,Ar), 8.10 (d, 2H, J=8.8 Hz, Ar), 8.24 (s, 1H, Ar), 10.36 (s, 1H, —NH—).

Example 138-[4-[((4-Acetylphenyl)carbamoylmethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthine(20)

¹H NMR (DMSO-d₆). 0.89 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.58 and 1.74 (2m,4H, 2×—CH₂—), 2.54 (s, 3H, —COCH₃), 3.87 and 4.02 (2t, 4H, J=6.8 Hz,2×—NCH₂—), 4.85 (s, 2H, —OCH₂—), 7.15 (d, 2H, J=8.8 Hz, Ar), 7.79 (d,2H, J=7.8 Hz, Ar), 7.96 (d, 2H, J=7.8 Hz, Ar), 8.09 (d, 2H, J=8.8 Hz,Ar), 10.48 (s, 1H, —NH—).

Example 148-[4-[((4-Methoxycarbonyl)phenylcarbamoylmethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthine(21)

¹H NMR (DMSO-d₆). 0.89 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.58 and 1.74 (2m,4H, 2×—CH₂—), 3.83 (s, 3H, —OCH₃), 3.86 and 4.02 (2t, 4H, J=6.8 Hz,2×—NCH₂—), 4.85 (s, 2H, —OCH₂—), 7.14 (d, 2H, J=8.8 Hz, Ar), 7.79 (d,2H, J=7.8 Hz, Ar), 7.96 (d, 2H, J=7.8 Hz, Ar), 8.09 (d, 2H, J=8.8 Hz,Ar), 10.50 (s, 1H, —NH—).

Example 158-[4-[((4-Carbamoyl)phenylcarbamoylmethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthine(22)

¹H NMR (DMSO-d₆). 0.89 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.58 and 1.74 (2m,4H, 2×—CH₂—), 3.87 and 4.02 (2t, 4H, J=6.8 Hz, 2×—NCH₂—), 4.82 (s, 2H,—OCH₂—), 7.14 (d, 2H, J=8.8 Hz, Ar), 7.26 (bs, 1H, —NH₂), 7.70 (d, 2H,J=7.8 Hz, Ar), 7.85 (m, 3H, Ar and —NH₂), 8.10 (d, 2H, J=8.8 Hz, Ar),10.35 (s, 1H, —NH—).

Example 168-[4-[((4-Methylcarbamoyl)phenylcarbamoylmethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthine(23)

A solution of 20 mg of compound 21 (0.0358 mmole) in 1 mL of 40% aqueousmethylamine was stirred at room temperature for 1 hour. The mixture wasevaporated to dryness under reduced pressure, and the residue waspurified by preparative silica gel TLC (CHCl₃:MeOH=20:1) andre-crystallized in MeOH/CH₂Cl₂ to afford 9 mg of compound 23. ¹H NMR(DMSO-d₆). 0.89 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.58 and 1.73 (2m, 4H,2×—CH₂—), 2.76 (s, 3H, —NHCH ₃) 3.86 and 4.01 (2t, 4H, J=6.8 Hz,2×—NCH₂—), 4.82 (s, 2H, —OCH₂—), 7.14 (d, 2H, J=8.8 Hz, Ar), 7.71 (d,2H, J=7.8 Hz, Ar), 7.81 (d, 2H, J=7.8 Hz, Ar), 8.09 (d, 2H, J=8.8 Hz,Ar), 8.33 (m, 1H, —NHCH₃), 10.34 (s, 1H, —NH—).

Example 178-[4-[((4-Carboxy)phenylcarbamoylmethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthine(24)

A suspension of 20 mg of compound 21 (0.0385 mmole) in 1 mL of 1 N NaOHsolution was stirred for 2 hours to turn to a clear solution. Themixture was neutralized by adding 1 mL of 1 N HCl solution. Theprecipitate was collected by filtration, and purified by low pressure(C18) column chromatography using linear gradient elution of 1 Mtriethylammonium acetate buffer (pH=7.0) and CH₃CN (90/10 to 40/60) toafford 10 mg of compound 24. ¹H NMR (DMSO-d₆). 0.89 (2t, 6H, J=7.8 Hz,2×—CH₃), 1.58 and 1.74 (2m, 4H, 2×—CH₂—), 3.87 and 4.01 (2t, 4H, J=6.8Hz, 2×—NCH₂—), 4.84 (s, 2H, —OCH₂—), 7.14 (d, 2H, J=8.8 Hz, Ar), 7.77(d, 2H, J=8.8 Hz, Ar), 7.92 (d, 2H, J=8.8 Hz, Ar), 8.09 (d, 2H, J=8.8Hz, Ar), 10.45 (s, 1H, —NH—).

Example 188-[4-[((4-Cyano)phenylcarbamoylmethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthine(27)

¹H NMR (DMSO-d₆). 0.89 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.58 and 1.74 (2m,4H, 2×—CH₂—), 3.86 and 4.01 (2t, 4H, J=6.8 Hz, 2×—NCH₂—), 4.85 (s, 2H,—OCH₂—), 7.13 (d, 2H, J=8.8 Hz, Ar), 7.80 (d, 2H, J=7.8 Hz, Ar), 7.84(d, 2H, J=7.8 Hz, Ar), 8.09 (d, 2H, J=8.8 Hz, Ar), 10.58 (s, 1H, —NH—).

Example 198-[4-[((4-Nitro)phenylcarbamoylmethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthine(28)

¹H NMR (DMSO-d₆). 0.89 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.58 and 1.74 (2m,4H, 2×—CH₂—), 3.87 and 4.02 (2t, 4H, J=6.8 Hz, 2×—NCH₂—), 4.89 (s, 2H,—OCH₂—), 7.15 (d, 2H, J=8.8 Hz, Ar), 7.91 (d, 2H, J=8.8 Hz, Ar), 8.10(d, 2H, J=8.8 Hz, Ar), 8.26 (d, 2H, J=8.8 Hz, Ar), 10.76 (s, 1H, —NH—).

Example 208-[4-[((4-Trifluoromethyl)phenylcarbamoylmethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthine(29)

¹H NMR (DMSO-d₆). 0.89 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.58 and 1.74 (2m,4H, 2×—CH₂—), 3.87 and 4.02 (2t, 4H, J=6.8 Hz, 2×—NCH₂—), 4.85 (s, 2H,—OCH₂—), 7.15 (d, 2H, J=8.8 Hz, Ar), 7.71 (d, 2H, J =7.8 Hz, Ar), 7.87(d, 2H, J=7.8 Hz, Ar), 8.09 (d, 2H, J=8.8 Hz, Ar), 10.51 (s, 1H, —NH—).

Example 218-[4-[((4-Fluoro)phenylcarbamoylmethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthine(30)

¹H NMR (DMSO-d₆). 0.89 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.58 and 1.74 (2m,4H, 2×—CH₂—), 3.87 and 4.02 (2t, 4H, J=6.8Hz, 2×—NCH₂—), 4.79 (s, 2H,—OCH₂—), 7.15 (d, 2H, J=8.8 Hz, Ar), 7.19 (d, 2H, J=8.8 Hz, Ar), 7.66(dd, 2H, J=5.9, 8.8 Hz, Ar), 8.10 (d, 2H, J=8.8 Hz, Ar), 10.20 (s, 1H,—NH—).

Example 228-[4-[((4-Chloro)phenylcarbamoylmethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthine(31)

¹H NMR (DMSO-d₆). 0.89 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.58 and 1.74 (2m,4H, 2×—CH₂—), 3.87 and 4.02 (2t, 4H, J=6.8 Hz, 2×—NCH₂—), 4.80 (s, 2H,—OCH₂—), 7.14 (d, 2H, J=7.8 Hz, Ar), 7.39 (d, 2H, J=7.8 Hz, Ar), 7.68(d, 2H, J=7.8 Hz, Ar), 8.09 (d, 2H, J=7.8 Hz, Ar), 10.27 (s, 1H, —NH—).

Example 238-[4-[((4-Bromo)phenylcarbamoylmethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthine(32)

¹H NMR (DMSO-d₆). 0.89 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.58 and 1.74 (2m,4H, 2×—CH₂—), 3.87 and 4.02 (2t, 4H, J=6.8 Hz, 2×—NCH₂—), 4.80 (s, 2H,—OCH₂—), 7.14 (d, 2H, J=8.8 Hz, Ar), 7.52 (d, 2H, J=8.8 Hz, Ar), 7.63(d, 2H, J=8.8 Hz, Ar), 8.09 (d, 2H, J=8.8 Hz, Ar), 10.27 (s, 1H, —NH—).

Example 248-[4-[((4-Iodo)phenylcarbamoylmethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthine(33)

¹H NMR (D)MSO-d₆). 0.89 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.58 and 1.74 (2m,4H, 2×—CH₂—), 3.87 and 4.02 (2t, 4H, J=6.8 Hz, 2×—NCH₂—), 4.79 (s, 2H,—OCH₂—), 7.14 (d, 2H, J=7.8 Hz, Ar), 7.49 (d, 2H, J=7.8 Hz, Ar), 7.68(d, 2H, J=7.8 Hz, Ar), 8.09 (d, 2H, J=7.8 Hz, Ar), 10.24 (s, 1H, —NH—).

Example 25 8-(4-(2-Carboxy-trans-vinyl)phenyl)-1,3-di-(n-propyl)xanthineN′,N′-[(1,2-Dimethyl)maleyl]hydrizide (34)

¹H NMR (CDCl₃). 1.01 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.72 and 1.89 (2m, 4H,2×—CH₂—), 2.05 (s, 6H, 2×—CH₃), 4.02 and 4.17 (2t, 4H, J=6.8 Hz,2×—NCH₂—), 6.67 (d, 1H, J=15.6 Hz, —CH═), 7.63 (d, 2H, J=8.8 Hz, Ar),7.74 (d, 1H, J=15.6 Hz, —CH═), 8.09 (d, 2H, J=8.8 Hz, Ar), 9.43 (s, 1H,—NH—).

Example 268-[4(2-(2-Acetylphenyl)carbamoyl-trans-vinyl)phenyl]-1,3-di-(n-propyl)xanthine(35)

¹H NMR (DMSO-d₆). 0.89 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.59 and 1.76 (2m,4H, 2×—CH₂—), 3.88 and 4.04 (2t, 4H, J=6.8 Hz, 2×—NCH₂—), 4.79 (d, 3H,J=4.9 Hz, —COCH₃), 6.93 (d, 1H, J=15.6 Hz, —CH═), 7.51 (d, 1H, J=15.6Hz, —CH═), 7.57 (t, 1H, J=7.8 Hz, Ar), 7.69 (t, 1H, J=7.8 Hz, Ar), 7.75(d, 2H, J=7.8 Hz, Ar), 8.03 (d, 2H, J=7.8 Hz, Ar), 8.18 (d, 2H, J=7.8Hz, Ar), 8.53 (t, 1H, J=5.8 Hz, —NH—).

Example 278-[4-(2-(2-Acetylphenyl)carbamoyl-trans-vinyl)phenyl]-1,3-di-(cyclohexylmethyl)xanthine(36)

¹H NMR (CDCl₃). 1.02-1.27 (m, 8H, c-Hex.), 1.45-1.72 (m, 14H, c-Hex.),4.00 and 4.08 (2d, 4H, J=6.8 Hz, 2×—NCH₂—), 4.96 (d, 3H, J=3.9 Hz,—COCH₃), 6.66 (d, 1H, J=15.6 Hz, —CH═), 6.86 (bs, 1H, —NH—), 7.54 (t,2H, J=7.8 Hz, Ar), 7.64-7.78 (m, 3H, —CH═and Ar), 8.06 (d, 2H, J=7.8 Hz,Ar), 8.24 (d, 2H, J=8.8 Hz, Ar).

Example 288-[4-(2-(2-Acetylphenyl)carbamoyl-trans-vinyl)phenyl]-1,3-dibenzylxanthine(37)

¹H NMR (DMSO-d₆) 4.79 (d, 3H, J=5.8 Hz, —COCH₃), 5.13 (s, 2H, —NCH₂—),5.27 (s, 2H, —NCH₂—), 6.93 (d, 1H, J=15.6 Hz, —CH═), 7.24-7.41 (m, 10H,2×-Ph), 7.46 (d, 1H, J=15.6 Hz, —CH═), 7.57 (t, 1H, J=8.8 Hz, Ar), 7.69(t, 1H, J=7.8 Hz, Ar), 7.75 (d, 2H, J=8.8 Hz, Ar), 8.03 (d, 2H, J=7.8Hz, Ar), 8.20 (d, 2H, J=7.8 Hz, Ar), 8.54 (t, 1H, J=5.8 Hz, —NH—).

Example 298-[4-[((2-Acetylphenyl)carbamoylmethyl)oxy]phenyl]-1,3-dibenzyl-xanthine(38)

¹H NMR (DMSO-d₆) 4.68 (s, 3H, —COCH₃), 4.71 (s, 2H, —OCH₂—), 5.12 (s,2H, —NCH₂—), 5.26 (s, 2H, —NCH₂—), 7.15 (d, 2H, J=8.8 Hz, Ar), 7.23-7.42(m, 10H, 2×-Ph), 7.55 (t, 1H, J=7.8 Hz, Ar), 7.68 (t, 1H, J=7.8 Hz, Ar),8.02 (d, 2H, J=7.8 Hz, Ar), 8.11 (d, 2H, J=8.8 Hz, Ar), 8.48 (t, 1H,J=4.8 Hz, —NH—).

Example 30 8-[4-[(Carboxymethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthineN-Acetylhydrazide (41)

¹H NMR (DMSO-d₆). 0.89 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.58 and 1.74 (2m,4H, 2×—CH₂—), 1.88 (s, 3H, CH₃CO—), 3.87 and 4.02 (2t, 4H, J=6.8 Hz,2×—NCH₂—), 4.68 (s, 2H, —OCH₂—), 7.11 (d, 2H, J=8.8 Hz, Ar), 8.08 (d,2H, J=8.8 Hz, Ar); MS-FAB (M+H⁺) 443.

Example 31 8-[4-[(Carboxymethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthineN-[(3-Carboxy)-n-propionyl]hydrazide (42)

¹H NMR (DMSO-d₆). 0.89 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.58 and 1.74 (2m,4H, 2×—CH₂—), 2.43 (m, 4H, —COCH₂CH₂CO—), 3.87 and 4.02 (2t, 4H, J=6.8Hz, 2×—NCH₂—), 4.67 (s, 2H, —OCH₂—), 7.11 (d, 2H,J=8.8 Hz, Ar), 8.08 (d,2H, J=8.8 Hz, Ar); MS-FAB (M+H⁺) 501.

Example 32 8-[4-[(Carboxymethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthineN,N-Succinylhydrazide (43)

¹H NMR (DMSO-d₆). 0.89 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.59 and 1.73 (2m,4H, 2×—CH₂—), 2.81 (s, 4H, CH₂CH₂), 3.87 and 4.03 (2t, 4H, J=6.8 Hz,2×—NCH₂—), 4.85 (s, 2H, —OCH₂—), 7.15 (d, 2H,J=8.8 Hz, Ar), 8.10 (d,2H,J=8.8 Hz, Ar); MS-FAB (M+H⁺) 483.

Example 33 8-[4-[(Carboxymethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthineN,N-[((2S)-Trifluoroacetamido)succinyl]hydrazide (44)

¹H NMR (DMSO-d₆). 0.89 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.58 and 1.74 (2m,4H, 2×—CH₂—), 2.70-2.90 (m, 2H, —CH₂—), 3.81 and 3.98 (2t, 4H, J=6.8 Hz,2×—NCH₂—), 4.69 (s, 2H, —OCH₂—), 4.95 (s, 1H, —CH—), 7.15 (d, 2H, J=8.8Hz, Ar), 8.10 (d, 2H,J=8.8Hz, Ar); MS-FAB (M+H⁺)594.

Example 34 8-[4-[(Carboxymethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthineN,N-[(2-Phenyl)glutaryl]hydrazide (45)

¹H NMR (CDCl₃). 1.05 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.75 and 1.90 (2m, 4H,2×—CH₂—), 2.3-2.5 and 2.8-3.1 (m, 5H, —CH— and 2×—CH₂—), 4.04 and 4.12(2t, 4H, J=6.8 Hz, 2×—NCH₂—), 4.70-4.90 (m, 2H, —OCH₂—), 6.6 (d, 2H,J=8.8 Hz, Ar), 7.08 (m, 2H, -Ph), 7.43 (m, 5H, -Ph and Ar); MS-FAB(M+H⁺) 573.

Example 35 8-[4-[(Carboxymethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthineN,N-Citraconylhydrazide (46)

¹H NMR (DMSO-d₆). 0.89 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.59 and 1.73 (2m,4H, 2×—CH₂—), 2.07 (s, 3H, CH₃), 3.87 and 4.03 (2t, 4H, J=6.8 Hz,2×—NCH₂—), 4.86 (s, 2H, —OCH₂—), 6.83 (s, 1H, ═CH—), 7.15 (d, 2H, J=8.8Hz, Ar), 8.10 (d, 2H, J=8.8 Hz, Ar); MS-FAB (M+H⁺) 495.

Example 36 8-[4-[(Carboxymethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthineN,N-[(1,2-Dimethyl)maleyl]hydrazide (47)

¹H NMR (DMSO-d₆). 0.89 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.58 and 1.74 (2m,4H, 2×—CH₂—), 1.97 (s, 6H, 2×—CH₃), 3.87 and 4.03 (2t, 4H, J=6.8 Hz,2×—NCH₂—), 4.86 (s, 2H, —OCH₂—), 7.14 (d, 2H, J=8.8 Hz, Ar), 8.10 (d,2H, J=8.8 Hz, Ar); MS-FAB (M+H⁺) 509.

Example 37 8-[4-[(Carboxymethyl)oxy]phenyl]-1H-3-(n-propyl)xanthineN,N-1(1,2-Dimethyl)maleyl]hydrazide (48)

¹H NMR (DMSO-d₆). 0.91 (t, 3H, J=7.8 Hz, 2×—CH₃), 1.73 (m, 2H, —CH₂—),1.97 (s, 6H, 2×—CH₃), 3.96 (t, 2H, J=6.8 Hz, 2×—NCH₂—), 4.85 (s, 2H,—OCH₂—), 7.14 (d, 2H, J=8.8 Hz, Ar), 8.09 (d, 2H, J=8.8 Hz, Ar); MS-EI(M⁺) 509, Calcd. for C₂₂H₂₂N₆O₆ 466.1601; Found 466.1580.

Example 38 8-[4-[(Carboxymethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthineN,N-[(2-Phenyl)maleyl]hydrazide (49)

¹H NMR (DMSO-d₆). 0.89 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.59 and 1.73 (2m,4H, 2×—CH₂—), 3.87 and 4.03 (2t, 4H, J =6.8 Hz, 2×—NCH₂—), 4.91 (s, 2H,—OCH₂—), 7.15 (d, 2H, J=8.8 Hz, Ar), 7.51 (s, 1H, ═CH—), 7.55-7.57 (m,3H, -Ph), 8.04-8.06 (m, 2H, -Ph), 8.11 (d, 2H, J=8.8 Hz, Ar); MS-FAB(M+H⁺) 557.

Example 39 8-[4-[(Carboxymethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthineN,N-[(1,2-Diphenyl)maleyl]hydrazide (50)

¹H NMR (DMSO-d₆). 0.89 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.59 and 1.73 (2m,4H, 2×—CH₂—), 3.87 and 4.03 (2t, 4H, J=6.8 Hz, 2×—NCH₂—), 4.94 (s, 2H,—OCH₂—), 7.15 (d, 2H, J=8.8 Hz, Ar), 7.45 (bs, 10H, 2×-Ph), 8.10 (d, 2H,J=8.8 Hz, Ar); MS-FAB (M+H⁺) 633.

Example 40 8-[4-[(Carboxymethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthineN-[2-((1-Carboxy)-cis-4-cyclohexene)-carbonyl]hydrazide (51)

¹H NMR (DMSO-d₆). 0.89 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.58 and 1.74 (2m,4H, 2×—CH₂—), 2.30-2.50 (m, 4H, 2×—CH₂—), 2.80-2.95 (m, 2H, 2×—CH—),3.83 and 3.90 (2t, 4H, J=6.8 Hz, 2×—NCH₂—), 4.66 (s, 2H, —OCH₂—), 5.63(s, 2H, 2×═CH—), 7.09 (d, 2H, J=8.8 Hz, Ar), 8.06 (d, 2H, J=8.8 Hz, Ar);MS-FAB (M+H⁺) 553.

Example 41 8-[4-[(Carboxymethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthineN,N-(cis-1,2,3,6-Tetrahydrophthaloyl)hydrazide (52)

¹H NMR (DMSO-d₆). 0.89 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.58 and 1.74 (2m,4H, 2×—CH₂—), 2.20-2.50 (m, 4H, 2×—CH₂—), 3.56 (m, 2H, 2×—CH—), 3.83 and3.90 (2t, 4H, J=6.8 Hz, 2×—NCH₂—), 4.66 (s, 2H, —OCH₂—), 5.89 (s, 2H,2×═CH—), 7.09 (d, 2H, J=8.8 Hz, Ar), 8.06 (d, 2H, J=8.8 Hz, Ar); MS-FAB(M+H⁺) 535.

Example 42 8-[4-[(Carboxymethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthineN-[2-((1-Carboxy)-1-cyclopentene)-carbonyl]hydrazide (53)

¹H NMR (DMSO-d₆). 0.89 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.58 and 1.74 (2m,4H, 2×—CH₂—), 1.87 (m, 2H, —CH₂—), 2.70 (m, 4H, 2×—CH₂—), 3.83 and 3.90(2t, 4H, J=6.8 Hz, 2×—NCH₂—), 4.71 (s, 2H, —OCH₂—), 7.09 (d, 2H, J=8.8Hz, Ar), 8.06 (d, 2H, J=8.8 Hz, Ar); MS-FAB (M+H⁺) 539.

Example 43 8-[4-[(Carboxymethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthineN,N-(1-Cyclopentene-1,2-dicarbonyl)hydrazide (54)

¹H NMR (DMSO-d₆). 0.89 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.58 and 1.74 (2m,4H, 2×—CH₂—), 2.40 (m, 2H, —CH1₂—), 2.67(4H, m, 2×—CH₂—), 3.81 and 3.98(2t, 4H, J=6.8 Hz, 2×—NCH₂—), 4.85 (s, 2H, —OCH₂—), 7.15 (d, 2H, J=8.8Hz, Ar), 8.1 (d, 2H, J 8.8 Hz, Ar); MS-FAB (M+H⁺) 521.

Example 44 8-[4-[(Carboxymethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthineN-[2-((1-Carboxy)-1-cyclohexene)-carbonyl]hydrazide (55)

¹H NMR (DMSO-d₆). 0.89 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.59 (m, 6H,3×—CH₂—), 1.74 (m, 2H, —CH₂—), 2.27 (m, 4H, 2×—CH₂—), 3.87 and 4.02 (2t,4H, J=6.8 Hz, 2×—NCH₂—), 4.68 (s, 2H, —OCH₂—), 7.09 (d, 2H, J=8.8 Hz,Ar), 8.06 (d, 2H, J=8.8 Hz, Ar); MS-FAB (M+H⁺) 553.

Example 45 8-[4-[(Carboxymethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthineN,N-(3,4,5,6-Tetrahydrophthaloyl)hydrazide (56)

¹H NMR (DMSO-d₆). 0.89 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.58 (m, 2H, —CH₂—),1.72 (m, 6H, 3×—CH₂—), 2.30 (m, 4H, 2×—CH₂—) 3.83 and 3.90 (2t, 4H,J=6.8 Hz, 2×—NCH₂—), 4.86 (s, 2H, —OCH₂—), 7.15 (d, 2H,J=8.8 Hz, Ar),8.12 (d, 2H, J=8.8 Hz, Ar); MS-FAB (M+H⁺) 535.

Example 46 8-[4-[(Carboxymethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthineN,N-Phthaloylhydrazide (57)

¹H NMR (DMSO-d₆). 0.89 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.58 and 1.74 (2m,4H, 2×—CH₂—), 3.87 and 4.02 (2t, 4H, J=6.8 Hz, 2×—NCH₂—), 4.75 (s, 2H,—OCH₂—), 7.14 (d, 2H, J=8.8 Hz, Ar), 7.57 (m, 4H, Ar), 8.09 (d, 2H,J=8.8 Hz, Ar); MS-FAB (M+H⁺) 531.

Example 47 8-[4-[(Carboxymethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthineN,N-Glutarylhydrazide (58)

¹H NMR (CDCl₃). 1.05 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.75 and 1.90 (2m, 4H,2×—CH₂—), 2.10-2.30 (m, 2H, —CH₂—), 2.80-3.10 (m, 4H, 2×—CH₂—), 4.05 and4.16 (2t, 4H, J=6.8 Hz, 2×—NCH₂—), 4.80 (s, 2H, —OCH₂—), 6.75 (d, 2H,J=8.8 Hz, Ar), 7.70 (d, 2H, J=8.8 Hz, Ar); MS-FAB (M+H⁺) 497.

Example 48 8-[4-[(Carboxymethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthineN,N-(3-Hydroxy)glutarylhydrazide (59)

¹H NMR (DMSO-d₆). 0.89 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.59 and 1.73 (2m,4H, 2×—CH₂—), 2.70-3.10 (m, 4H, 2×—CH₂—), 3.87 and 4.03 (2t, 4H, J=6.8Hz, —NCH₂—), 4.21 (bs, 1H, —CHOH—), 4.77 (s, 2H, —OCH₂—), 7.15 (d, 2H,J=8.8 Hz, Ar), 8.1 (d, 2H, J=8.8 Hz, Ar); MS-FAB (M+H⁺) 513.

Example 49 8-[4-[(Carboxymethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthineN-[(4-Carboxy-(2S)-Trifluoroacetamido)-n-butanoyl]hydrazide (60)

A mixture of compound 4f (10 mg, 0.025 mmol), 7.6 mg of L-N-Boc-glutamicacid 5-tert-butyl ester (0.025 mmole), 7 mg of HOBt (0.05 mmole), 19 mgof DIPEA (0.15 mmole) and 15 mg of EDAC (0.078 mmole) in 1 mL of dry DMFwas stirred for 8 hours at 25° C. The DMF was removed by nitrogenstream. The residue was washed with 1 mL of 1 M NaHCO₃ solution anddried overnight. The crude product was suspended in 0.5 mL of CHCl₃ and0.5 mL of TFA added. After stirring for 30 minutes at 25° C., themixture was concentrated to dryness and dried under high vacuum. Theresidue was dissolved in 0.5 mL of TFAA and the solution was stirred for30 minutes at 25° C. The reaction mixture was concentrated to dryness,and the residue was purified by preparative TLC (CHCl₃:MeOH=10:1) toafford 6 mg of compound 60 as a white solid (yield 40%). ¹H NMR(DMSO-d₆). 0.89 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.59 and 1.73 (2m, 4H,—CH₂—), 1.90-2.30 (m, 4H, 2×—CH₂—), 3.87 and 4.02 (2t, 4H, J=6.8 Hz,2×—NCH₂—), 4.12 (m, 1H, —CH—), 4.68 (s, 2H, —OCH₂—), 7.08 (d, 2H, J=8.8Hz, Ar), 8.06 (d, 2H, J=8.8 Hz, Ar); MS-FAB (M+H⁺) 626.

Example 50 8-[4-[(Carboxymethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthineN,N-((2S)-Trifluoroacetamido)glutaryl]hydrazide (61)

A mixture of compound 60 (10 mg, 0.016 mmol), 7 mg of HOBt (0.05 mmole),19 mg of DIPEA (0.15 mmole) and 15 mg of EDAC (0.078 mmole) in 1 mL ofdry DMF was stirred overnight at 25° C. The reaction mixture wasconcentrated to dryness, and the residue was purified by preparative TLC(CHCl₃:MeOH=10:1) to afford 5 mg of compound 61 as a white solid (yield53%). ¹H NMR (DMSO-d₆). 0.89 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.59 and 1.73(2m, 4H, 2×—CH₂—), 1.90-2.30 (m, 4H, 2×—CH₂—), 3.87 and 4.02 (2t, 4H,J=6.8 Hz, 2×—NCH₂—), 4.81 (s, 2H, —OCH₂—), 4.18 (m, 1H, —CH—), 7.15 (d,2H, J=8.8 Hz, Ar), 8.1 (d, 2H, J=8.8 Hz, Ar); MS-FAB (M+H⁺) 608.

Example 51 8-[4-[(Carboxymethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthineN-(N-tert-Butoxycarbonyl-L-leucinyl)hydrazide 62)

¹H NMR (DMSO-d₆). 0.89 (m, 13H, 2×—CH₃ and (CH₃)₂CH—), 1.35 (s, 9H,Boc), 1.42 (m, 2H, —CH₂—), 1.58 and 1.74 (2m, 4H, 2×—CH₂—), 3.85 and 4.0(2t, 4H, J=6.8 Hz, 2×—NCH₂—), 4.12 (m, 1H, —CH—), 4.64 (s, 2H, —OCH₂—),7.06 (d, 2H, J=8.8 Hz, Ar), 8.05 (d, 2H, J=8.8 Hz, Ar); MS-FAB (M+H⁺)614.

Example 52 8-[4-[(Carboxymethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthineN-(N-tert-Butoxycarbonyl-L-methionyl)hydrazide (63)

¹H NMR (DMSO-d₆). 0.89 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.25 (m, 2H, —CH₂—),1.37 (s, 9H, Boc), 1.58 and 1.74 (2m, 4H, 2×—CH₂—), 1.88 (m, 2H, —CH₂—,2.03 (s, 3H, —SCH₃), 3.81 and 3.98 (2t, 4H, J=6.8 Hz, 2×—NCH₂—), 4.15(m, 1H, —CH—), 4.68 (s, 2H, —OCH₂—), 7.03 (d, 2H, J=8.8 Hz, Ar), 8.03(d, 2H, J=8.8 Hz, Ar); MS-FAB (M+H⁺) 632.

Example 53 8-[4-[(Carboxymethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthineN-(N-Benzyloxycarbonyl-glycylglycinyl)hydrazide (64)

¹H NMR (DMSO-d₆). 0.89 (2t, 6H, J=7.8 Hz, 2×—CH₃), 1.58 and 1.74 (2m,4H, 2×—CH₂—), 3.67 (m, 1H, —CH₂— in glycine), 3.81 (m, 3H, —NCH₂— and—CH₂— in glycine), 3.98 (t, 2H, J=6.8 Hz, —NCH₂—), 4.64 (s, 2H, —OCH₂—),5.03(s, 2H, —OCH ₂-Ph), 7.03 (d, 2H, J=8.8 Hz, Ar), 7.3-7.5 (m, 5H,-Ph), 8.03 (d, 2H, J=8.8 Hz, Ar); MS-FAB (M+H⁺) 649.

Example 54 8-[4-[(Carboxymethyl)oxy]phenyl]-1H-3-(n-propyl)xanthineMethyl Ester (65)

To a suspension of 3.2 g of 2,5-dioxo-4-amino-3-propyl tetrahydropyrimidine, 66 [prepared according to the method described in Papesch etal., J. Org. Chem., 16, 1879-1890 (1951)] (18.9 mmole), 1.5 mL ofglacial acetic acid and 3.4 mL of 6 N HCl in 50 mL of water was addeddropwise a solution of 1.38 g of sodium nitrite (20 mmole) in 5 mL ofwater at 0° C. The mixture was stirred for 1 hour and the pinkprecipitate was collected by filtration to afford 3.17 g of nitro-amine,67 (yield 78%). ¹H NMR (DMSO-d₆) 0.87 (t, 3H, J=7.8 Hz, —CH₃), 1.51 (m,2H, —CH₂—), 3.72 (t, 2H, J=6.8 Hz, —NCH₂—), 9.12 (s, 11H, —NH₂).

0.086 g of nitro-amine, 67 (0.4 mmole) was hydrogenated with 10% Pd/C in5 mL of MeOH under H₂ atmosphere (1 atm) at 25° C. until the pink colordisappeared (30 min). After the removal of the balloon of H₂, 5 mL ofDMF was added and the mixture was stirred for 10 min and filteredthrough a Celite bed.

To the solution of crude diamine, 68 was added 0.078 g of methyl4-formylphenyloxyacetate (0.4 mmole) and 0.5 mL of acetic acid. Themixture was heated at 50° C. for 30 min, evaporated under reducedpressure and suspended in 20 mL of ether. The yellow precipitate(mixture of 69 and 65) was collected by filtration, dissolved in 5 mL ofDMF and treated with 1 mL of aqueous solution of 0.085 g of sodiumperiodate (0.4 mmole) for 2 hours. After evaporation, the product waspurified by crystallization in MeOH/H₂0 to afford 0.048 g of xanthine,65 (yield 34%). 1H NMR (DMSO-d₆). 0.90 (t, 3H, J=7.8 Hz, —CH₃), 1.72 (m,2H, —CH₂—), 3.71 (s, 3H, —OCH₃), 3.95 (t, 2H, J=6.8 Hz, —NCH₂—), 4.89(s, 2H, —OCH₂—), 7.08 (d, 2H, J=8.8 Hz, Ar), 8.05 (d, 2H, J=8.8 Hz, Ar),11.07 (s, 1H, —NH); MS-EI (M⁺) 358, Calcd. for C₁₇H₁₈N₄O₅ 358.1277;Found 358.1269.

Example 55 8-[4-[(Carboxymethyl)oxy]phenyl]-1H-3-(n-propyl)xanthineHydrazide (70)

A solution of 0.05 g of xanthine 65 (0.14 mmole) and 0.5 mL of hydrazineanhydrous in 2 mL of dry DMF was heated overnight at 50° C. Afterevaporation, the residue was suspended in MeOH and the white precipitatewas collected by filtration to give 0.025 g of 70 (yield 50%). m.p.=267°C.; ¹H NMR (DMSO-d₆). 0.90 (t, 3H, J=7.8 Hz, —CH₃), 1.72 (m, 2H, —CH₂—),3.71 (s, 3H, —OCH₃), 3.95 (t, 2H, J=6.8 Hz, —NCH₂—), 4.34 (bs, 2H, NH₂),4.56 (s, 2H, —OCH₂—), 7.08 (d, 2H, J=8.8 Hz, Ar), 8.05 (d, 2H, J=8.8 Hz,Ar), 9.39 (s, 1H, —NH); MS-EI (M⁺) 358, Calcd. for C₁₆H₁₈N₆O₄ 358.1389;Found 358.1389.

Table 5 contains data for yields and characterization of the xanthinecompounds of the invention. Table 6 contains data for elemental analysisof the xanthine compounds of the invention.

TABLE 5 The yields and chemical characterization of xanthinederivatives. Compound % yield m.p. (° C.) MS Formula Analysis  7 13 >310EI:482 C₂₇H₂₂N₄O₅ HRMS^(a) 10 40 >310 FAB:479 C₂₈H₂₂N₄O₄ C,H,N 12 71301-302 CI:462 C₂₅H₂₇N₅O₄ C,H,N 13 41  268 CI:476 C₂₆H₂₉N₅O₄ C,H,N 14 46269-270 EI:551 C₃₂H₃₃N₅O₄ C,H,N 15 55  230 EI:565 C₃₃H₃₅N₅O₄ C,H,N 16 49 215 FAB:476 C₂₆H₂₉N₅O₄ C,H,N 17 13  225 CI:558 C₂₇H₃₅N₅O₈ C,H,N 18 68 294 EI:503 C₂₇H₂₉N₅O₅ C,H,N 19 29 269-270 EI:503 C₂₇H₂₉N₅O₅ HRMS^(a) 2029 309-310 EI:503 C₂₇H₂₉N₅O₅·0.23H₂O C,H,N 21 56 >310 CI:520 C₂₇H₂₉N₅O₆C,H,N 22 19 >310 CI:505 C₂₆H₂₈N₆O₅ C,H,N 23 45 >310 FAB:519C₂₇H₃₀N₆O₅·1.8CH₂Cl₂ C,H,N 24 51 >310 FAB:506 C₂₆H₂₇N₅O₆·0.60CH₂Cl₂C,H,N 27 44 >310 CI:487 C₂₆H₂₆N₆O₄ C,H,N 28 31  307 CI:507C₂₅H₂₆N₆O₆·0.43CH₃OH C,H,N 29 44 >310 CI:530 C₂₆H₂₆F₃N₅O₄·0.26CH₃OHC,H,N 30 48  298 CI:480 C₂₅H₂₆FN₅O₄ C,H,N 31 31  309 CI:496C₂₅H₂₆ClN₅O₄·0.26(CH₃)₂CO C,H,N 32 36 >310 CI:540 C₂₅H₂₆BrN₅O₄ C,H,N 3313 >310 CI:588 C₂₅H₂₆IN₅O₄·0.60CH₃OH C,H,N 4c 79 >310 FAB:509 C₂₅H₂₈N₆O₆C,H,N 34 49 302-303 EI:504 C₂₆H₂₈N₆O₅ C,H,N 35 42 281-283 CI:500C₂₈H₂₉N₅O₄·0.27MeOH C,H,N 36 33  305 FAB:608 C₃₆H₄₁N₅O₄ HRMS^(a) 37 76308-309 CI:596 C₃₆H₂₉N₅O₄·0.60H₂O C,H,N 38 18  284 EI:599 C₃₅H₂₉N₅O₅HRMS^(a) ^(a)) High-resolution mass in EI or FAB⁺ mode (m/z) determinedto be within acceptable limits: 7: calcd, 482.1590; found, 482.1597, 19:calcd, 503.2169; found, 503.2169, 36: calcd, 608.3237; found, 608.3251;38: calcd, 599.2169; found, 599.2171.

TABLE 6 Elemental Analysis of Xanthine Derivatives Compound MW No.Formula (anhyd) Calculated (% or HRMS) Found (% or HRMS)  7 C₂₇H₂₂N₄O₅482.49 482.1590 482.1597 10 C₂₈H₂₂N₄O₄ 478.50 C70.28, H4.63, N11.70C70.16, H4.72, N11.72 12 C₂₅H₂₇N₅O₄ 461.52 C65.06, H5.90, N15.17 C65.04,H5.93, N15.20 13 C₂₆H₂₉N₅O₄ 475.54 C65.66, H6.15, N14.72 C65.70, H6.22,N14.72 14 C₃₂H₃₃N₅O₄ 551.64 C69.67, H6.03, N12.69 C69.60, H6.08, N12.6615 C₃₃H₃₅N₅O₄ 565.67 C70.06, H6.24, N12.38 C70.01, H6.33, N12.35 16C₂₆H₂₉N₅O₄ 475.54 C65.66, H6.15, N14.72 C65.45, H6.23, N14.68 17C₂₇H₃₃N₅O₈ 557.60 C58.15, H6.33, N12.56 C57.93, H6.38, N12.41 18C₂₇H₂₉N₅O₅ 503.55 C64.40, H5.81, N13.90 C64.24, H5.83, N13.87 19C₂₇H₂₉N₅O₅ 503.55 503.2169 503.2169 20 C₂₇H₂₉N₅O₅ 503.55 C64.40, H5.81,N13.90 C₂₇H₂₉N₅O₅·0.23H₂O 507.70 C63.88, H5.85, N13.79 C63.74, H5.77,N13.80 21 C₂₇H₂₉N₅O₆ 519.55 C62.41, H5.63, N13.48 C62.58, H5.67, N13.3622 C₂₆H₂₈N₆O₅ 504.54 C61.89, H5.59, N16.65 C60.64, H5.66, N15.58 23C₂₇H₃₀N₆O₅ 518.57 C62.53, H5.83, N16.20 C₂₇H₃₀N₆O₅·1.80CH₂Cl₂ 671.45C51.51, H5.04, N12.51 C51.75, H4.92, N12.77 24 C₂₆H₂₇N₅O₆ 505.53 C61.77,H5.38, N13.85 C₂₆H₂₇N₅O₆·0.60CH₂Cl₂ 556.49 C57.41, H5.11, N12.58 C57.12,H5.18, N12.46 27 C₂₆H₂₆N₆O₄ 486.53 C64.18, H5.39, N17.27 C64.27, H5.47,N17.03 28 C₂₅H₂₆N₆O₆ 506.51 C59.28, H5.17, N16.59 C₂₅H₂₆N₆O₆·0.43CH₃OH520.30 C58.70, H5.37, N16.15 C58.63, H5.26, N15.98 29 C₂₆H₂₆F₃N₅O₄529.51 C58.97, H4.95, N13.22 C₂₆H₂₆F₃N₅O₄·0.26CH₃OH 537.85 C58.64,H5.07, N13.02 C58.74, H5.07, N12.96 30 C₂₅H₂₆FN₅O₄ 479.51 C62.62, H5.47,N14.60 C62.39, H5.49, N14.31 31 C₂₅H₂₆ClN₅O₄ 495.96 C60.54, H5.28,N14.12 C₂₅H₂₆ClN₅O_(4·0.26(CH) ₃)₂CO 511.07 C60.59, H5.44, N13.70C60.59, H5.40, N13.62 32 C₂₅H₂₆BrN₅O₄ 540.41 C55.56, H4.85, N12.95C55.28, N4.89, N12.70 33 C₂₅H₂₆IN₅O₄ 587.41 C51.11, H4.46, N11.92C₂₅H₂₆IN₅O₄·0.60CH₃OH 606.64 C50.68, H4.72, N11.54 C50.48, H4.40, N11.284c C₂₅H₂₈N₆O₆ 508.53 C59.04, H5.55, N16.52 C58.79, H5.50, N16.48 34C₂₆H₂₈N₆O₅ 504.54 C61.89, H5.59, N16.65 C62.18, H5.86, N16.31 35C₂₈H₂₉N₅O₄ 499.56 C67.31, H5.85, N14.01 C₂₈H₂₉N₅O₄·0.27MeOH 508.22C66.81, H5.97, N13.78 C66.73, H5.87, N13.61 36 C₃₆H₄₁N₅O₄ 607.75608.3237 (M + H) 608.3251 37 C₃₆H₂₉N₅O₄ 595.65 C72.59, H4.91, N11.75C₃₆H₂₉N₅O₄·0.60H₂O 606.47 C71.30, H5.02, N11.55 C71.48, H4.98, N11.45 38C₃₅H₂₉N₅O₅ 599.64 599.2169 599.2171

Example 56 Prevention of Myocardial Necrosis Following Ninety Minute LADOcclusion by8-[4-[((4-Cyano)phenylcarbamoylmethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthine(27)

The compounds of the invention were tested for their ability to blockA_(2B) receptors to show that mast cell degranulation can be reduced orprevented. In addition, this example shows that these antagonists couldprevent or markedly attenuate the extent of myocardial infarction thatoccurred during coronary artery occlusion.

The left anterior descending (LAD) coronary artery of a group of dogswas isolated and encircled with a snare occluder. The dogs LAD arteryblood supply was occluded for 90 minutes. The test solutions wereadministered intracoronary beginning immediately prior to the 90 minuteocclusion interval and continued for two hours post-reperfusion (FIG.6). One group of three dogs were administered a solution containing the(4-cyano)phenyl compound, prepared in Example 18, infused at aconcentration of 200 nM at a rate of 1.0 mL /min. by intracoronary(i.c.) infusion into the LAD. A second group of four dogs wereadministered a solution containing the vehicle (carrier). Regionalmyocardial blood flow was measured at baseline, during LAD occlusion andfor 2 hrs after reperfusion using radiolabeled microspheres (mic).

The results are illustrated in FIGS. 7 and 8. These figures show thatthe infusion of the test compound during the 90 minute occlusiondramatically attenuated infarct size compared with dogs that wereuntreated.

All patents, patent applications, books and literature cited in thespecification are hereby incorporated by reference in their entirety. Inthe case of any inconsistencies, the present disclosure, including anydefinitions therein will prevail. The invention has been described withreference to various specific and preferred embodiments and techniques.However, it should be understood that many variations and modificationsmay be made while remaining within the spirit and scope of theinvention.

What is claimed is:
 1. A compound of formula I:

wherein R, and R¹ are independently hydrogen, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₃-C₈)cycloalkyl,(C₄-C₁₆)cycloalkylalkyl, heterocycle, (C₆-C₁₀)aryl, (C₇-C₁₈)aralkyl orheteroaryl;

X is (C₁-C₈)alkylene, (C₂-C₈)alkenylene, (C₂-C₈)alkynylene, wherein oneof the carbon atoms in the alkylene, alkenylene or alkynylene groups isoptionally replaced with a group having the formula —O—, —N(R⁴)C(O)—,—OC(O)—, —S—, —S(O)— or —SO₂—, R² is hydrogen, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₃-C₈)cycloalkyl,(C₄-C₁₆)cycloalkylalkyl, (C₆-C₁₀)aryl, (C₇-C₁₈)aralkyl, heterocycle orheteroaryl; wherein R² is optionally substituted with one or moresubstituents selected from the group consisting of —OH, —SH, —NH₂,—NHR⁷, —CN, —COOH and —SO₃H, wherein R⁴, and R⁷ are independentlyhydrogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl,(C₇-C₁₈)aralkyl or halo(C₁-C₆)alkyl; and wherein R⁸ is hydrogen,(C₃-C₈)cycloalkyl, (C₄-C₁₆)cycloalkylalkyl, (C₇-C₁₈)aralkyl, heterocycleor heteroaryl, each optionally substituted with one or moresubstituents, wherein the substituents independently are oxo,(C₁-C₈)alkyl, halo(C₁-C₆)alkyl, (C₂-C₈)alkenyl, (C₆-C₁₀)aryl,(C₇-C₁₈)aralkyl, heteroaryl, halo, —OR¹⁵, —CN, —NO₂, —CO₂R¹⁵, —OC(O)R¹⁶,—C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴, —C(O)NR¹⁷R¹⁸, —SR¹⁹, —SO₂R²⁰ or—SO₃H; or R⁸ is (C₆-C₁₀)aryl, substituted with one or more substituentsindependently selected from the group consisting of (C₁-C₈)alkyl,halo(C₁-C₆)alkyl, (C₂-C₈)alkenyl, (C₇-C₁₈)aralkyl, heteroaryl, —OR¹⁵,—CN, —NO₂, —CO₂R¹⁵, —OC(O)R¹⁶, —C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴,—C(O)NR¹⁷R¹⁸, —SR¹⁹, —SO₂R²⁰ and —SO₃H; and wherein R⁹ is(C₃-C₈)cycloalkyl, (C₄-C₁₆)cycloalkylalkyl, heterocycle or heteroaryl,each optionally substituted with one or more substituents, wherein thesubstituents independently are oxo, (C₁-C₈)alkyl, halo(C₁-C₆)alkyl,(C₂-C₈)alkenyl, (C₆-C₁₀)aryl, (C₇-C₁₈)aralkyl, heteroaryl, —OR¹⁵, halo,—CN, —NO₂, CO₂R¹⁵, —OC(O)R¹⁶, —C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴,—C(O)NR¹⁷R¹⁸, —SR¹⁹, —SO₂R²⁰ or —SO₃H; or R⁹ is (C₆-C₁₀)aryl,substituted with one or more substituents independently selected fromthe group consisting of (C₁-C₈)alkyl, halo(C₁-C₆)alkyl, (C₂-C₈)alkenyl,(C₇-C₁₈)aralkyl, heteroaryl, —OR¹⁵, —CN, —NO₂, O₂R¹⁵, —OC(O)R¹⁶,—C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴, —C(O)NR¹⁷R¹⁸, —SR¹⁹, and —SO₂R²⁰,and wherein R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²³ and R²⁴ areindependently hydrogen (C₁-₈)alkyl, (C₂-C₈)alkenyl, (C₃-C₈)cycloalkyl,(C₆-C₈)aryl, (C₇-C₁₈)aralkyl or halo(C₁-C₆)alkyl; provided that when Rand R⁸ are both H, and R¹ and R² are both alkyl, R⁹ is not methylphenylor hydroxyphenyl; or a pharmaceutically acceptable salt thereof.
 2. Thecompound according to claim 1, wherein R and R¹ are independentlyhydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy,(C₅-C₆)cycloalkyl, (C₆-C₁₀)cycloalkylalkyl, heterocycle, (C₆)aryl,(C₇-C₁₀)aralkyl or heteroaryl; X is (C₁-₆)alkylene, (C₂-C₆)alkenylene,(C₂-C₆)alkynylene, wherein one of the carbon atoms in the alkylene,alkenylene or alkynylene groups is optionally replaced with a grouphaving the formula —O—, —N(R⁴)C(O)—, —OC(O)—, —S—, —S(O)— or —SO₂—; R²is hydrogen, (C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl,(C₁-C₄)alkoxy, (C₅-C₆)cycloalkyl, (C₆-C₁₀)cycloalkylalkyl, (C₆)aryl,(C₇-C₁₀)aralkyl or a heterocycle; wherein R⁴, and R⁷ are independentlyhydrogen, (C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₅-C₆)cycloalkyl, (C₆)aryl,(C₇-C₁₀)aralkyl or halo(C₁-C₆)alkyl groups; and wherein R⁸ is hydrogen,(C₃-C₆)cycloalkyl, (C₃-C₁₀)cycloalkylalkyl, (C₇-C₁₀)aralky heterocycleor heteroaryl, each optionally substituted with one or moresubstituents, wherein the substituents independently are oxo,(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₆)aryl,(C₇-C₁₀)aralkyl, heteroaryl, halo, —OR¹⁵, —CN, —NO₂, —CO₂R¹⁵, —OC(O)R¹⁶,—C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴, —C(O)NR¹⁷R¹⁸, —SR¹⁹, —SO₂R²⁰ or—SO₃H; or R⁸ is (C₆-C₁₀)aryl, substituted with one or more substituentsindependently selected from the group consisting of (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₇-C₁₀)aralkyl, heteroaryl, halo,—OR¹⁵, —CN, —NO₂, —CO₂R¹⁵, —OC(O)R¹⁶, —C(O)R¹⁶, —NR¹³R¹⁴,—N(R²³)C(O)R²⁴, —C(O)NR¹⁷R¹⁸, —SR¹⁹, —SO₂R²⁰ and —SO₃H; or R⁹ is(C₃-C₆)cycloalkyl, (C₄-C₁₀)cycloalkylalkyl, heterocycle or heteroaryl,each optionally substituted with one or more substituents, wherein thesubstituents independently are oxo, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₆)aryl, (C₇-C₁₀)aralkyl, heteroaryl, halo, —OR¹⁵, —CN,—NO₂, —CO₂R¹⁵, —OC(O)R¹⁶, —C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴,—C(O)NR¹⁷R¹⁸, —SR¹⁹, —SO₂R²⁰ or —SO₃H; or R⁹ is (C₆-C₁₀)aryl,substituted with one or more substituents independently selected fromthe group consisting of (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₇-C₁₀)aralkyl, heteroaryl, halo, —OR¹⁵, —CN, —NO₂, —CO₂R¹⁵, —OC(O)R¹⁶,—C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴, —C(O)NR¹⁷R¹⁸, —SR¹⁹, and —SO₂R²⁰. 3.The compound according to claim 2, wherein R, R¹ and R² areindependently hydrogen, (C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl,(C₁-C₄)alkoxy, (C₅-C₆)cycloalkyl, (C₆-C₁₀)cycloalkylalkyl, (C₆)aryl, or(C₇-C₁₀)aralkyl;

X is O—(C₁-C₇)alkylene, O—(C₂-C₇)alkenylene, (C₁-C₈)alkylene or(C₂-C₈)alkenylene; wherein R⁹ is (C₃-C₆)cycloalkyl,(C₄-C₁₀)cycloalkylalkyl, heterocycle or heteroaryl, each optionallysubstituted with one or more substituents, wherein the substituentsindependently are oxo, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₆)aryl, (C₇-C₁₀)aralkyl, heteroaryl, halo, —OR¹⁵, —CN, —NO₂, —CO₂R¹⁵,—OC(O)R¹⁶, —C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴, —C(O)NR¹⁷R¹⁸, —SR¹⁹,—SO₂R²⁰ or —SO₃H; or R⁹ is (C₆-C₁₀)aryl, substituted with one or moresubstituents independently selected from the group consisting of(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₇-C₁₀)aralkyl,heteroaryl, halo, —OR¹⁵, —CN, —NO₂, —CO₂R¹⁵, —OC(O)R¹⁶, —C(O)R¹⁶,—NR¹³R¹⁴, —N(R²³)C(O)R²⁴, —C(O)NR¹⁷R¹⁸, —SR¹⁹, and —SO₂R²⁰.
 4. Acompound of formula I:

R is hydrogen, (C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl,(C₁-C₄)alkoxy, (C₅-C₆)cycloalkyl, (C₆-C₁₀)cycloalkylalkyl, (C₆)aryl, or(C₇-C₁₀)aralkyl; R¹ and R² are independently —CH₂CH₃, —CH₂CH═CH₂,—CH₂CH₂CH₃ or cyclohexylmethyl; and wherein —Z—X— is

R⁸ is hydrogen or (C₇-C₁₈)aralkyl, optionally substituted with one ormore substituents, wherein the substituents independently are oxo,(C₁-C₈)alkyl, halo(C₁-C₆)alkyl, (C₂-C₈)alkenyl, (C₆-C₁₀)aryl,(C₇-C₁₈)aralkyl, heteroaryl, halo, —OR¹⁵, —CN, —NO₂, —CO₂R¹⁵, —OC(O)R¹⁶,—C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴, —C(O)NR¹⁷R¹⁸, —SR¹⁹, —SO₂R²⁰ or—SO₃H; or R⁸ is (C₆-C₁₀)aryl: wherein the aryl is substituted with oneor more substituents independently selected from the group consisting of(C₁-C₈)alkyl, halo(C₁-C₆)alkyl, (C₂-C₈)alkenyl, (C₇-C₁₈)aralkyl,heteroaryl, —OR¹⁵, —CN, —NO₂, —CO₂R¹⁵, —OC(O)R¹⁶, —C(O)R¹⁶, —NR¹³R¹⁴,—N(R²³)C(O)R²⁴, —C(O)R¹⁷R¹⁸, —SR¹⁹, —SO₂R²⁰ and —SO₃H; R⁹ is


5. The compound according to claim 3, wherein —Z—X— is

R¹ and R² are independently —CH₂CH₃, —CH₂CH═CH₂, —CH₂CH₂CH₃ orcyclohexylmethyl.
 6. The compound according to claim 5, wherein aryl isphenyl and aralkyl is benzyl.
 7. The compound according to claim 6,wherein R⁹ is phenyl substituted with 1-3 substituents that areindependently trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl,(C₁-C₄)alkyl, (C₂-C₄)alkenyl, benzyl, F, Cl, Br, I, —CN, —NO₂, —CO₂R¹⁵,—C(O)R¹⁶, —NR¹³R¹⁴ or —C(O)NR¹⁷R¹⁸.
 8. The compound according to claim7, wherein R⁸ is hydrogen and R⁹ is phenyl substituted with 1-3substituents that are independently F, Cl, Br, I, —CN, —COOH, —C(O)OCH₃,—C(O)CH₂CH₃, —C(O)CH₃, —C(O)NH₂ or —C(O)NHCH₃.
 9. The compound accordingto claim 5, wherein —NR⁸R⁹ is


10. The compound according to claim 9, wherein R is H, R¹ and R² areeach —CH₂CH═CH₂, and R⁹ is 4-cyanophenyl.
 11. The compound according toclaim 9, wherein R is H, R¹ and R² are each —CH₂CH₂CH₃, and R⁹ is3-carboxy-4-hydroxyphenyl or 3-acetylphenyl.
 12. A pharmaceuticalcomposition comprising a compound of formula I:

wherein R, is hydrogen, (C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl,(C₁-C₄)alkoxy, (C₅-C₆)cycloalkyl, (C₆-C₁₀)cycloalkylalkyl, (C₆)aryl, or(C₇-C₁₀)aralkyl; wherein —Z—X— is

R⁸ is hydrogen or (C₇-C₁₈)aralkyl, optionally substituted with one ormore substituents, wherein the substituents independently are oxo,(C₁-C₈)alkyl, halo(C₁-C₆)alkyl, (C₂-C₈)alkenyl, (C₆-C₁₀)aryl,(C₇-C₁₈)aralkyl, heteroaryl, halo, —OR¹⁵, —CN, —NO₂, —CO₂R¹⁵, —OC(O)R¹⁶,—C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴, —C(O)NR¹⁷R¹⁸, —SR¹⁹, —SO₂R²⁰ or—SO₃H; or R⁸ is (C₆-C₁₀)aryl: wherein the aryl is substituted with oneor more substituents independently selected from the group consisting of(C₁-C₈)alkyl, halo(C₁-C₆)alkyl, (C₂-C₈)alkenyl, (C₇-C₁₈)aralkyl,heteroaryl, —OR¹⁵, —CN, —NO₂, —CO₂R¹⁵, —OC(O)R¹⁶, —C(O)R¹⁶, —NR¹³R¹⁴,—N(R²³)C(O)R²⁴, —C(O)NR¹⁷R¹⁸, —SR¹⁹, —SO₂R²⁰ and —SO₃H; R⁹ is

or a pharmaceutically acceptable salt thereof in combination with apharmaceutically acceptable carrier.
 13. A method for treating diarrhea,insulin resistance, diabetes, ischemia/reprefusion injuries, diabeticretinopathy or hyperbaric oxygen-induced retinopathy, comprisingadministering an effective amount of a compound of formula I:

wherein R, and R¹ are independently hydrogen, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-₈)alkoxy, (C₃-C₈)cycloalkyl,(C₄-C₆)cycloalkylalkyl, heterocycle, (C₆-C₁₀)aryl, (C₇-C₁₈)aralkyl orheteroaryl;

X is (C₁-C₈)alkylene, (C₂-C₈)alkenylene, (C₂-C₈)alkynylene, wherein oneof the carbon atoms in the alkylene, alkenylene or alkynylene groups isoptionally replaced with a group having the formula —O—, —N(R⁴)C(O)—,—OC(O)—, —S—, —S(O)— or —SO₂—, R² is hydrogen, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₃-C₈)cycloalkyl,(C₄-C₁₆)cycloalkylalkyl, (C₆-C₁₀)aryl, (C₇-C₁₈)aralkyl, heterocycle orheteroaryl; wherein R² is optionally substituted with one or moresubstituents selected from the group consisting of —OH, —SH, —NH₂,—NHR⁷, —CN, —COOH and —SO₃H, wherein R⁴, and R⁷ are independentlyhydrogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl,(C₇-C₁₈)aralkyl or halo(C₁-C₆)alkyl; and wherein R⁸ is hydrogen,(C₃-C₈)cycloalkyl, (C₄-C₁₆)cycloalkylalkyl, (C₇-C₁₈)aralkyl, heterocycleor heteroaryl, each optionally substituted with one or moresubstituents, wherein the substituents independently are oxo,(C₁-C₈)alkyl, halo(C₁-C₆)alkyl, (C₂-C₈)alkenyl, (C₆-C₁₀)aryl,(C₇-C₁₈)aralkyl, heteroaryl, halo, —OR¹⁵, —CN, —NO₂, —CO₂R¹⁵, —OC(O)R¹⁶,—C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴, —C(O)NR¹⁷R¹⁸, —SR¹⁹, —SO₂R²⁰ or—SO₃H; or R⁸ is (C₆-C₁₀)aryl, substituted with one or more substituentsindependently selected from the group consisting of (C₁-C₈)alkyl,halo(C₁-C₆)alkyl, (C₂-C₈)alkenyl, (C₇-C₁₈)aralkyl, heteroaryl, —OR¹⁵,—CN, —NO₂, —CO₂R¹⁵, —OC(O)R¹⁶, —OC(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴,—C(O)NR¹⁷R¹⁸, —SR¹⁹, —SO₂R²⁰ and —SO₃H; and wherein R⁹ is(C₃-C₈)cycloalkyl, (C₄-C₁₆)cycloalkylalkyl, heterocycle or heteroaryl,each optionally substituted with one or more substituents, wherein thesubstituents independently are oxo, (C₁-C₈)alkyl, halo(C₁-C₆)alkyl,(C₂-C₈)alkenyl, (C₆-C₁₀)aryl, (C₇-C₁₈)aralkyl, heteroaryl —OR¹⁵, halo,—CN, —NO₂, —CO₂R¹⁵, —OC(O)R¹⁶, —C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴,—C(O)NR¹⁷R¹⁸, —SR¹⁹, —SO₂R²⁰ or —SO₃H; or R⁹ is (C₆-C₁₀)aryl,substituted with one or more substituents independently selected fromthe group consisting of (C₁-C₈)alkyl, halo(C₁-C₆)alkyl, (C₂-C₈)alkenyl,(C₇-C₁₈)aralkyl, heteroaryl, —OR¹⁵, —CN, —NO₂, —CO₂R¹⁵, —OC(O)R¹⁶,—C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴, —C(O)NR¹⁷R¹⁸, —SR¹⁹, and —SO₂R²⁰; ora pharmaceutically acceptable salt thereof to a mammal in need of suchtreatment.
 14. A method for antagonizing adenosine A_(2B) receptors inmammalian tissue comprising contacting the receptors with an effectiveamount of a compound of claim 1 or 4 wherein the amount is effective toantagonize the adenosine A_(2B) receptors in the tissue.
 15. Thecompound of claim 1 or 4, wherein one of the atoms of said compound isreplaced by its radionuclide.
 16. The compound of claim 15, wherein theradionuclide is tritium, or radioactive iodine.
 17. A pharmaceuticalcomposition comprising a compound of formula I:

wherein R, and R¹ are independently hydrogen, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-₈)alkoxy, (C₃-C₈)cycloalkyl,(C₄-C₁₆)cycloalkylalkyl, heterocycle, (C₆-C₁₀)aryl, (C₇-C₁₈)aralkyl orheteroaryl;

X is (C₁-C₈)alkylene, (C₂-C₈)alkenylene, (C₂-C₈)alkynylene, wherein oneof the carbon atoms in the alkylene, alkenylene or alkynylene groups isoptionally replaced with a group having the formula —O—, —N(R⁴)C(O)—,—OC(O)—, —S—, —S(O)— or —SO₂—, R² is hydrogen, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₃-C₈)cycloalkyl,(C₄-C₁₆)cycloalkylalkyl, (C₆-C₁₀)aryl, (C₇-C₁₈)aralkyl, heterocycleheteroaryl; wherein R² is optionally substituted with one or moresubstituents selected from the group consisting of —OH, —SH, —NH₂,—NHR⁷, —CN, —COOH and —SO₃H, wherein R⁴, and R⁷ are independentlyhydrogen (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl,(C₇-C₁₈)aralkyl or halo(C₁-C₆)alkyl; and wherein R⁸ is hydrogen,(C₃-C₈)cycloalkyl, (C₄-C₁₆)cycloalkylalkyl, (C₇-C₁₈)aralkyl, heterocycleor heteroaryl, each optionally substituted with one or moresubstituents, wherein the substituents independently are oxo,(C₁-C₈)alkyl, halo(C₁-C₆)alkyl, (C₂-C₈)alkenyl, (C₆-C₁₀)aryl,(C₇-C₁₈)aralkyl, heteroaryl, halo, —OR¹⁵, —CN, —NO₂, —CO₂R¹⁵, —OC(O)R¹⁶,—C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴, —C(O)NR¹⁷R¹⁸, —SR¹⁹, —SO₂R^(2o) or—SO₃H; or R⁸ is (C₆-C₁₀)aryl, substituted with one or more substituentsindependently selected from the group consisting of (C₁-C₈)alkyl,halo(C₁-C₆)alkyl, (C₂-C₈)alkenyl, (C₇-C₁₈)aralkyl, heteroaryl, —OR¹⁵,—CN, —NO₂, —CO₂R¹⁵, —OC(O)R¹⁶, —C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴,C(O)NR¹⁷R¹⁸, —SR¹⁹, —SO₂R²⁰ and —SO₃H; and wherein R⁹ is(C₃-C₈)cycloalkyl, (C₄-C₁₆)cycloalkylalkyl, heterocycle or heteroaryl,each optionally substituted with one or more substituents, wherein thesubstituents independently are oxo, (C₁-C₈)alkyl, halo(C₁-C₆)alkyl,(C₂-C₈)alkenyl, (C₆-C₁₀)aryl, (C₇-C₁₈)aralkyl, heteroaryl, —OR¹⁵, halo,—CN, —NO₂, —CO₂R¹⁵, —OC(O)R¹⁶, —OC(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴,—C(O)NR¹⁷R¹⁸, —SR¹⁹, —SO₂R²⁰ or —SO₃H; or R⁹ is (C₆-C₁₀)aryl,substituted with one or more substituents independently selected fromthe group consisting of (C₁-C₈)alkyl, halo(C₁-C₆)alkyl, (C₂-C₈)alkenyl,(C₇-C₁₈)aralklyl, heteroaryl, —OR¹⁵, —CN, —NO₂, —C₂R¹⁵, —OC(O)R¹⁶,—C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴, —C(O)NR¹⁷R¹⁸, —SR¹⁹, and —SO₂R²⁰,and wherein R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²³ and R²⁴ areindependently hydrogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₃-C₈)cycloalkyl,(C₆-C₁₀)aryl, (C₇-C₁₈)aralkyl or halo(C₁-C₆)alkyl; provided that when Rand R⁸ are both H, and R¹ and R² are both alkyl, R⁹ is not methylphenylor hydroxyphenyl; or a pharmaceutically acceptable salt thereof incombination with a pharmaceutically acceptable carrier.
 18. Thecomposition according to claim 17, wherein R and R¹ are independentlyhydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy,(C₅-C₆)cycloalkyl, (C₆-C₁₀)cycloalkylalkyl, heterocycle, (C₆)aryl,(C₇-C₁₀)aralkyl or heteroaryl; X is (C₁-C₆)alkylene, (C₂-C₆)alkenylene,(C₂-C₆)alkynylene, wherein one of the carbon atoms in the alkylene,alkenylene or alkynylene groups is optionally replaced with a grouphaving the formula —O—, —N(R⁴)C(O)—, —OC(O)—, —S—, —S(O)— or —SO₂—; R²is hydrogen, (C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl,(C₁-C₄)alkoxy, (C₅-C₆)cycloalkyl, (C₆-C₁₀)cycloalkylalkyl, (C₆)aryl,(C₇-C₁₀)aralkyl or a heterocycle; wherein R⁴, and R⁷ are independentlyhydrogen, (C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₅-C₆)cycloalkyl, (C₆)aryl,(C₇-C₁₀)aralkyl or halo(C₁-C₆)alkyl groups; and wherein R⁸ is hydrogen,(C₃-C₆)cycloalkyl, (C₄-C₁₀)cycloalkylalkyl, (C₇-C₁₀)aralkyl, heterocycleor heteroaryl, each optionally substituted with one or moresubstituents, wherein the substituents independently are oxo,(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₆)aryl,(C₇-C₁₀)aralkyl, heteroaryl, halo, —OR¹⁵, —CN, —NO₂, —CO₂R¹⁵, —OC(O)R¹⁶,—C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴, —C(O)NR¹⁷R¹⁸, —SR¹⁹, —SO₂R²⁰ or—SO₃H; or R⁸ is (C₆-C₁₀)aryl, substituted with one or more substituentsindependently selected from the group consisting of (C₁-C₆)alkyl,halo(C₁-₆)alkyl, (C₂-C₆)alkenyl, (C₇-C₁₀)aralkyl, heteroaryl, halo,—OR¹⁵, —CN, —NO₂, —CO₂R¹⁵, —OC(O)R¹⁶, —C(O)R¹⁶, —NR¹³R¹⁴,—N(R²³)C(O)R²⁴, —C(O)NR¹⁷R¹⁸, —SR¹⁹, —SO₂R²⁰ and —SO₃H; or R⁹ is(C₃-C₆)cycloalkyl, (C₄-C₁₀)cycloalkylalkyl, heterocycle or heteroaryl,each optionally substituted with one or more substituents, wherein thesubstituents independently are oxo, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₆)aryl, (C₇-C₁₈)aralkyl, heteroaryl, halo, —OR¹⁵, —CN,—NO₂, —CO₂R¹⁵, —OC(O)R¹⁶, —C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴,—C(O)NR¹⁷R¹⁸, —SR¹⁹, —SO₂R²⁰ or —SO₃H; or R⁹ is (C₆-C₁₀)aryl,substituted with one or more substituents independently selected fromthe group consisting of (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₇-C₁₀)aralkyl, heteroaryl, halo, —OR¹⁵, —CN, —NO₂, —CO₂R¹⁵, —OC(O)R¹⁶,—C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴, —C(O)NR¹⁷R¹⁸, —SR¹⁹, and —SO₂R²⁰.19. The composition according to claim 18, wherein R, R¹ and R² areindependently hydrogen, (C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl,(C₁-C₄)alkoxy, (C₅-C₆)cycloalkyl, (C₆-C₁₀)cycloalkylalkyl, (C₆)aryl, or(C₇-C₁₀)aralkyl;

X is O—(C₁-C₇)alkylene, O—(C₂-C₇)alkenylene, (C₁-C₈)alylene or(C₂-C₈)alkenylene; wherein R⁹ is (C₃-C₆)cycloalkyl,(C₄-C₁₀)cycloalkylalkyl, heterocycle or heteroaryl each optionallysubstituted with one or more substituents, wherein the substituentsindependently are oxo, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₆)aryl, (C₇-C₁₀)aralkyl, heteroaryl, halo, —OR¹⁵, —CN, —NO₂, —CO₂R¹⁵,—OC(O)¹⁶, —C(O)R¹⁶, —NR¹³ R¹⁴, —N(R²³)C(O)R²⁴, —C(O)NR¹⁷R¹⁸, —SR¹⁹,—SO₂R²⁰ or —SO₃H; or R⁹ is (C₆-C₁₀)aryl, substituted with one or moresubstituents independently selected from the group consisting of(C₁-₆)alkyl, halo(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₇-C₁₀)aralkyl,heteroaryl, halo, —OR¹⁵, —CN, —NO₂, —CO₂R¹⁵, —OC(O)R¹⁶, —C(O)R¹⁶,—NR¹³R¹⁴, —N(R²³)C(O)R²⁴, —C(O)NR¹⁷R¹⁸, —SO₂R²⁰.
 20. The compositionaccording to claim 19, wherein —Z—X— is

and R¹ and R² are independently —CH₂C₃, —CH₂CH═CH, —CH₂CH₂CH₃ orcyclohexylmethyl.
 21. The composition according to claim 20, whereinaryl is phenyl and aralkyl is benzyl.
 22. The composition according toclaim 21, wherein R⁹ is phenyl substituted with 1-3 substituents thatare independently trifluoromethyl, 2,2,2-trifluoroethyl,pentafluoroethyl, alkenyl, benzyl, F, Cl, Br, I, —CN, —NO₂, —CO₂R¹⁵,—C(O)R¹⁶, —NR¹³R¹⁴ or —C(O)NR¹⁷R¹⁸.
 23. The composition according toclaim 22, wherein R⁸ is hydrogen and R⁹ is phenyl substituted with 1-3substituents that are independently F, Cl, Br, I, —CN, —COOH, —CO₂CH₃,—C(O)CH₂CH₃, —C(O)CH₃, —C(O)NH₂ or —C(O)NHCH₃.
 24. The compositionaccording to claim 20, wherein —NR⁸R⁹ is:


25. The composition according to claim 24, wherein R and R⁸ are each H,R¹and R² are each —CH₂CH═CH₂, and R⁹ is 4-cyanophenyl.
 26. Thecomposition according to claim 25, wherein R and R⁸ are each H, R¹and R²are each —CH₂CH₂CH₃, and R⁹ is 3-carboxy-4-hydroxyphenyl or3-acetylphenyl.
 27. A method for treating asthma comprisingadministering an effective amount of a compound of claim 1 or 4 to amammal in need of such treatment.